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The emerging role of 27-hydroxycholesterol in cancer development and progression: An update
Saade Abdalkareem Jasim a, Hamzah H. Kzarb, Mohammed Haider Hamad “, Irfan Ahmad ª, Moaed E. Al-Gazally , Shukhrat Ziyadullaev , R. Sivaraman &, Mohammed Abed Jawadh, Ali Thaeer Hammid’, Khulood H. Oudaha, Sajad Karampoor k,*, Rasoul Mirzaei 1,”
ª Medical Laboratory Techniques Department, Al-maarif University College, Al-anbar-Ramadi, Iraq
b Veterinary medicine college, Al-Qasim green University, Al-Qasim, Iraq
” Medical Laboratory Techniques Department, Al Mustaqbal University college, Babylon, Iraq
d Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
e College of Medicine, University of Al-Ameed, Karbala, Iraq Professor, Doctor of Medical Sciences, No.1 Department of Internal Diseases, Vice-rector for Scientific Affairs and Innovations, Samarkand State Medical University, Amir Temur Street 18, Samarkand, Uzbekistan
8 Department of Mathematics, Institution of Dwaraka Doss Goverdhan Doss Vaishnav College, Arumbakkam, Chennai, University of Madras, Chennai, India
h Department of pharmacy, Al-Nisour University College, Baghdad, Iraq
i Computer Engineering Techniques Department, Faculty of Information Technology, Imam Ja’afar Al-Sadiq University, Baghdad, Iraq
Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University Thi-Qar, Iraq
k Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
l Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| ARTICLE INFO | ABSTRACT |
|---|---|
| Keywords: 27-hydroxycholesterol CYP27A1 Estrogen receptor Liver X receptor Cancer | Oxysterols are cholesterol metabolites generated in the liver and other peripheral tissues as a mechanism of removing excess cholesterol. Oxysterols have a wide range of biological functions, including the regulation of sphingolipid metabolism, platelet aggregation, and apoptosis. However, it has been found that metabolites derived from cholesterol play essential functions in cancer development and immunological suppression. In this regard, research indicates that 27-hydroxycholesterol (27-HC) might act as an estrogen, promoting the growth of estrogen receptor (ER) positive breast cancer cells. The capacity of cholesterol to dynamically modulate signaling |
Abbreviations: CYP27A1, Cytochrome P450 Family 27 Subfamily A Member 1; ER, Estrogen receptor; 27-HC, 27-hydroxycholesterol; LXR, Liver X receptor; EVs, extracellular vehicles; ERß, ER-beta; ERa, ER-alpha; PR, progesterone receptor; CYP7B1, Cytochrome P450 Family 7 Subfamily B Member 1; PMNs, Poly- morphonuclear neutrophils; T-yo cells, Gamma delta T cells; ABCA1, ATP Binding Cassette Subfamily A Member 1; PD-L1, Programmed death-ligand 1; MMP9, matrix metalloproteinase 9; ROS, reactive oxygen species; MCF7, Michigan Cancer Foundation-7; RECK, Reversion Inducing Cysteine Rich Protein With Kazal Motifs; STAT3, Signal transducer and activator of transcription 3; EMT, Epithelial-mesenchymal transition; TNBC, triple-negative breast cancer; MDA-MB 231, M.D. Anderson - Metastatic Breast 231; 7-KC, 7-ketocholesterol; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; Akt, serine/threonine- protein kinase; SREBP-1, sterol regulatory element-binding protein-1; HMEC-1, human microvascular endothelial cell line 1; HUVEC, human umbilical vein endothelial cell; EndMT, endothelial-to-mesenchymal transition; PTDSS2, Phosphatidylserine synthase 2; IDO1, indoleamine 2,3-dioxygenase 1; THRA, thyroid hormone receptor alpha; MIR613, MicroRNA 613; DNMT3B, DNA methyltransferase 3 beta; IGF, Insulin-like growth factor; EGF, epidermal growth factor; GPER, G Protein-Coupled Estrogen Receptor; SkBr3, Sloan-Kettering breast cancer 3; MDM2, Mouse double minute 2 homolog; LNCaP, Lymph Node Carcinoma of the Prostate, PC3, Prostate Cancer 3; PHTPP, Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]-pyrimidin-3-yl]phenol; IL6, Interleukin 6; JAK, Janus kinase; TNM, tumour, node, metastasis; 25-EC, 25- epoxycholesterol; HGC-27, human Gastric cancer cell line 27; MAPK, mitogen-activated protein kinase; PFS, progression-free survival time; GW3965, synthetic selective, active non-steroidal LXR agonist, LAC, Lung adenocarcinoma; PPIB, peptidylprolyl isomerase B; NF-KB, Nuclear factor kappa B; FGF2, Fibroblast Growth Factor 2; NFATC1, Nuclear Factor Of Activated T Cells 1; GRP75, glucose-regulated protein 75; NRF2, Nuclear factor-erythroid factor 2- related factor 2, HO-1, heme oxygenase-1; NQO1, NAD(P)H Quinone Dehydrogenase 1; HIF-1a, Hypoxia-inducible factor 1-alpha; c-myc, cellular c-myc (is a pro- tein coding gene); cFos, a proto-oncogene; BTT, benign thyroid tumor, papillary thyroid carcinoma, PTC; PDTC/ATC, papillary differentiated thyroid carcinoma/ anaplastic thyroid carcinoma; HEK 293, human embryonic kidney cell 293; DHCR24, 24-Dehydrocholesterol reductase; Rap1, Ras-related protein Rap1; GSK-36, Glycogen synthase kinase-3B.
* Corresponding authors at: Gastrointestinal, and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran. (Sajad Karampoor). Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.(Rasoul Mirzaei). E-mail addresses: karampour.s@iums.ac.ir, sajadkarampour1987@gmail.com (S. Karampoor), rasul.micro92@gmail.com (R. Mirzaei).
https://doi.org/10.1016/j.intimp.2022.109074
molecules inside the membrane and particular metabolites serving as signaling molecules are two possible contributory processes. 27-HC is a significant metabolite produced mainly through the CYP27A1 (Cytochrome P450 27A1) enzyme. 27-HC maintains cholesterol balance biologically by promoting cholesterol efflux via the liver X receptor (LXR) and suppressing de novo cholesterol production through the Insulin-induced Genes (INSIGs). It has been demonstrated that 27-HC is able to function as a selective ER regulator. Moreover, enhanced 27-HC production is in favor of the growth of end-stage malignancies in the brain, thyroid organs, and colon, as shown in breast cancer, probably due to pro-survival and pro-inflammatory signaling induced by unbalanced levels of oxysterols. However, the actual role of 27-HC in cancer promotion and progression remains debatable, and many studies are warranted to be performed to unravel the precise function of these molecules. This review article will summarize the latest evidence on the deleterious or beneficial functions of 27-HC in various types of cancer, such as breast cancer, prostate cancer, colon cancer, gastric cancer, ovarian cancer, endometrial cancer, lung cancer, melanoma, glioblastoma, thyroid cancer, adrenocortical cancer, and hepatocellular carcinoma.
1. Introduction
Cholesterol and its metabolites are important in membrane physi- ology, nutritional absorption from food, reproductive biology, salt and water balance, calcium metabolism, and stress response [1]. Cholesterol has been essential for regulating mammalian cell longevity and cell cycle progression [2]. More importantly, cholesterol is far more than a membrane material; it is a precursor to steroid hormones and bile acids, which could also begin or accelerate prostate, colon, and breast tumors [3-5]. Cholesterol could also influence signaling pathways implicated in carcinogenesis and tumor development through the covalent alteration of proteins, such as Smoothened and Hedgehog, and encouraging the production of a particular type of membrane microdomains [6-9]. Cholesterol can be converted into oxysterols (cholesterol derivates), which influence the regulating scheme of cholesterol production [10]. In human peripheral blood, 27-hydroxycholesterol (27-HC) is the most prevalent type of oxysterols [11,12]. The findings support the idea that oxysterols have a physiological role in a variety of manners and bio- logical systems. In this context, emerging experimental data suggest that 27-HC has a wide antiviral action as well as a modulatory role in human immunity [13-15]. 27-HC has also been linked to the progression and metastasis of various tumors [16]. Oxysterol (e.g., 27-HC) can bind to the liver X receptor (LXR), alpha and beta, and estrogen receptor (ER) [10]. 27-HC is a selective estrogen receptor modulator (SERM) that acts as an agonist for ER in the breast while acting as an antagonist in other tissues, such as the bone and cardiovascular system [17]. 27-HC is the first SERM molecule to be produced within the human body. Since its discovery as a SERM, 27-HC has been associated with several patho- logical conditions, such as cancer, Alzheimer’s disease, and osteoporosis [18]. In the setting of ER-positive breast cancer, the attachment of 27- HC to ER promotes cancer development, whereas LXR activity pro- motes metastasis [19,20]. In the context of ER positive breast cancer, it has been demonstrated that monocytes at the site of onset are crucial for the production of 27-HC, which can be exploited by ER positive breast cancer cells to maintain the potential for increasing migration [21,22]).
27-HC is capable of functioning as an ER inducer in ER-positive breast tumors, activation of ERs, and associated signaling systems [23]. In stromal cells with breast cancer, the cytochrome P450 enzyme oxidase sterol 27-hydroxylase A1 (CYP27A1) enzymes catalyze choles- terol hydrolysis into 27-HC [23]. As a SERM, 27-HC adheres to intra- cellular ER in ER positive tumor cells, stimulating cell growth via the Akt/ mammalian target of rapamycin (mTOR) axis or Akt/Glycogen synthase kinase-3 (GSK-3)/-catenin signaling processes [23]. In breast cancer cells, CYP27A1-rich entering macrophages promote the produc- tion of 27-HC. Also, increased CYP27A1 activity in biopsied breast cancers is associated with a higher tumor stage [23]. Additionally, the action of the 27-HC metabolic enzyme Cytochrome P450 Family 7 Subfamily B Member 1 (CYP7B1) is lower in breast cancer [20,24]. An enhanced amount of 27-HC throughout the tumor microenvironment corresponds to tumorigenesis and aggression of breast cancer as a result of stimulated 27-HC anabolism and repressed catabolismo24,25]. 27- HC was initially identified as a biological modulator of the impacts of
high cholesterol dietary on the formation of human malignancies [20]. This oxysterol-derived molecule has also been demonstrated to play a role in endocrine tolerance of breast cancer since 27-HC treatment in- creases the proliferation of MCF7 cells (tamoxifen-resistant) to mini- mum levels similar to estradiol (E2) or tamoxifen [20]. Subsequently, the functions of 27-HC in several types of cancer, particularly lung cancer, colon cancer, prostate cancer, and glioblastoma, were inten- sively addressed [17]. Studies indicated that 27-HC has both cancer cell- intrinsic and -extrinsic impacts on tumor growth [26]. In this review article, we will discuss the most recent research on the destructive or protective functions of 27-HC in various malignancies, including breast cancer, prostate cancer, colon cancer, gastric cancer, ovarian cancer, endometrial cancer, lung cancer, melanoma, glioblastoma, thyroid cancer, adrenocortical cancer, and hepatocellular carcinoma (HCC).
2. Cholesterol and cancer connection
Cholesterol is a significant lipid compound required for various biochemical functions, both physiological and pathophysiological [27]. Cholesterol is necessary for keeping the structure and activity of bio- membranes, notably membrane trafficking, endocytosis, and signaling; also, it is a vital element for the cell membrane [27,28]. Within the cell, cholesterol, dispersed unevenly throughout the organelles, controls the immune response and serves as a precursor of vitamin D and androgens [29]. For an extended period, cholesterol levels, which are intimately tied to changes in lifestyle, are highly correlated with cardiovascular diseases [30]. Very low-density lipoproteins (VLDL), Low-density lipo- protein (LDL), high-density lipoprotein (HDL), triglycerides, and total cholesterol (TC) are all components of the lipoprotein profile [31]. Cholesterol levels, particularly total cholesterol and LDL, have already been implicated in developing numerous types of cancer, including prostate cancer, colon cancer, and testicular cancer [32]. In this sense, challenging epidemiological findings on cholesterol concentrations and the risk of breast cancer have been described [33-35].
Enhanced blood cholesterol levels have been implicated in the development of malignancies, including testicular cancer, prostate cancer, rectal cancer, and colon cancer [36,37]. A significant association between hypercholesterolemia and tumorigenesis is further supported by many investigations on cancer models [38]. A high cholesterol regimen was shown to diminish tumor establishment latency and accelerate tumor development and propagation in the mouse mammary tumor virus-polyoma middle tumor-antigen (MMTV-PyMT) breast can- cer model [39]. In another investigation, cholesterol enhanced colon cancer growth in mice treated with azoxymethane by triggering the NLR family pyrin domain containing 3 (NLRP3) inflammasome [40]. Ac- cording to Moon and colleagues [37], diet-induced hypercholesterole- mia promotes metastasis in a prostate cancer cell line (PC-3) via the upregulation of the metastasis-related protein IQ Motif Containing GTPase Activating Protein 1 (IQGAP1). Cholesterol, as a vital element of the cell membranes, might well be tightly associated with membrane receptors, by which cholesterol might directly stimulate oncogenic pathways. The Hedgehog axis is a very well cancer-related signaling
pathway regulated through smoothened G-protein-coupled receptors (GPCRs) [41,42]. Cholesterol has been shown to promote oncogenic Hedgehog signaling by specifically adhering to the Smoothened receptor [43,44]. Signaling activity is linked to cell differentiation, cell growth, and tumor development [45]. In C6 glioblastoma cells, another survey suggests that cholesterol may penetrate the binding domain of another kind of membrane GPCR, the adenosine A2A receptor (A2AR) [46]. The pattern of ligand-receptor binding in malignancies was found to be the same.
3. 27-hydroxycholesterol biosynthesis
27-HC is an oxygenated cholesterol metabolite and a substrate for bile acid production and transports sterols from peripheral tissues to the liver [47]. 27-HC is the most circulating oxysterol whose blood level is proportional to cholesterol [17]. In healthy individuals, the concentra- tion of 27-HC ranges from 0.2 to 0.9 uM, but its concentration is dramatically elevated in aged subjects and individuals with hypercho- lesterolemia [17]. The enzyme sterol 27-hydroxylase produces 27-HC in most extra-hepatic organs and is predominantly expressed in the liver, but to a lesser extent, in peripheral organs [48]. This enzyme is required for the digestion of steroid side chains, and a hereditary deficit of the enzyme results in diminished bile acid production in humans [47]. CYP27A1 and CYP7B1 are abundantly expressed in the liver to convert excess cholesterol into bile acids, but they are also found in the lung, brain, adipose, and other tissues [17]. CYP27A1 facilitates oxidative degradation of steroid side chains in the conventional pathway of liver bile acid biosynthesis in the liver and cholesterol hydroxylation to 3- beta-hydroxy-5-cholestenic acid and 27-HC in most organs [49,50]. Based on the evidence from macrophages, it has been suggested that the enzyme CYP27A1 may help protect against atherosclerosis by convert- ing excess cholesterol to 27-HC [51]. Hepatocytes can transport and transform oxysterols into bile acid [52]. The correlation of the genetic variants of CYP27A1 with the deposition of extra levels of cholesterol and early atherosclerotic events in cerebrotendinous xanthomatosis (CTX) patients supports the involvement of CYP27A1 in cholesterol balance as well as defense against atherosclerotic disorders [53]. 27-HC can be further oxidized into 7-hydroxy-3-oxo-4-cholestenoic acid when CYP27A1 levels are high [54]. Unlike cholesterol, 27-HC may pass through the plasma membrane and be scavenged by lipoproteins [54]. It should be noted the origin of 27-HC in the peripheral tissues and cir- culation is different from that in the liver. The majority of 27-HC is produced in the liver, but almost all 27-HC synthesized in the liver is converted to bile acids and does not go into circulation [47,55]. The 27- HC is a substrate for the production of bile acids and traditionally transports sterols from peripheral tissues to the liver [47]. Circulating levels of 27-HC are thought to predominantly come from extrahepatic sources and rise with age, especially beyond the age of 30 [56,57]. In both rats and humans, circulating 27-HC levels are lower in females than in men, and this is very certainly due to the elevation of Cyp7b1 expression by E2 and ER [58,59]. Studies in mice show how the lipid status affects the 27-HC concentration in tissues, mirroring the re- lationships between circulating cholesterol levels and 27-HC reported in people. The total 27-HC content of the aorta increases threefold when wild-type mice are fed a high cholesterol/high fat diet. Even in the absence of the formation of atherosclerotic lesions, hypercholesterole- mia generates 27-HC in the vasculature, with an estimated aortic tissue density of up to 1.0 g/ml [55]. So, with hypercholesterolemia, vascular 27-HC content rises to levels that alter ER function as predicted [47]. Notably, 27-HC may not serve as a traditional endocrine agent, but rather, it may be a significant intracrine or paracrine modulator and be present in larger amounts in critical organs. Collectively, these findings suggest that the physiological role of 27-HC may be cell- and tissue- specific, and that it may thus be regarded a possible endogenous SERM. Furthermore, CYP27A1 is abundantly expressed in macrophages, brain, vascular, and gut, demonstrating that 27-HC concentrations are
regulated locally in non-hepatic cell types [60]. CTX occurs when in- dividuals with CYP27A1 mutations build cholesterol and cholestanol in tendons and the brainThis is because decreased bile synthesis of bile by impairing CYP27A1 increases cholesterol 7x-hydroxylase activity [61]. Individuals with CYP27A1 genetic abnormalities and defective 27-HC hydroxylation exhibit circulating concentrations of 2-3 uM 27-HC compared with normal amounts [62,63]. Cyp7b1 -/- mice had higher levels of 27-HC and 25-hydroxycholesterol (25-HC) by 3-5 folds. Regardless of having reduced 27-HC and hydroxylation of 25-HC, CYP27A1 -/- animals had normal plasma cholesterol and triglyceride levels, most likely due to the increased bile acid production via alter- native mechanisms [64]. In addition to its pivotal contribution to oxy- sterol hepatic metabolism, this enzyme is present in other organs, including the renal and lung, which might catalyze 7«-hydroxylation of 27-HC, 25-HC, as well as other substrates locally [65].
4. The receptors and signaling of 27-hydroxycholesterol
Oxysterol ligands are implicated in activating the orphan nuclear receptors LXR & and ß [66]. LXRa is abundantly expressed, with the maximum levels in the liver and macrophages, kidney, gut, and adipose tissue. The LXRs establish complexes with the retinoid X receptor (RXR) and play a critical performance in sterol assimilation in the gastroin- testinal (GI) tract, bile acid production, start reversing cholesterol transfer, biliary neutral sterol efflux, liver lipid metabolism, and the production of newly emerging HDL-LXRs also has been established as silencers of the expression of inflammatory genes in macrophages [67- 69]. By means of atherosclerosis-prone mice models, researchers discovered that LXRs had an anti-atherogenic activity [70,71]. Never- theless, LXR activation with artificial analogs, such as T0901317 causes hepatic steatosis and elevated serum triglyceride levels through lipo- genic function, which is a potential cardiovascular risk [72]. This limi- tation could be addressed by using intestine-specific LXR stimulation, which results in lower cholesterol absorption, as established through pharmacologic and genetic manipulation [73]. Although it is debatable if oxysterols effectively operate as endogenous ligands of the LXR, Chen et al. [74], by using upregulation of cholesterol sulfotransferase(an oxysterol catabolizing enzyme), demonstrated the inhibition of LXR activation in various cultured mammalian cell lines. However, it did not seem to be affecting the receptor sensitivity to T0901317 (a non-sterol LXR agonist) [75]. Shafaati and colleagues [76] recently demonstrated CYP46A1 upregulation in mouse models under the actin promoter. This led to considerably greater concentrations of 24S-Hydroxycholesterol (24S-HC) and the inability to trigger target genes of LXR in the liver or brain. The above evidence challenges the role of 24S-HC as a signif- icant intrinsic LXR activator in vitro.
27-HC is synthesized catalytically from cholesterol via CYP27A1 and metabolized to bile acids through CYP7B1 [60]. As a result, any inter- ruption in this transit corridor could influence 27-HC synthesis. The expression of CYP27A1 and CYP7B1 enzymes predominantly occurs in the liver, which helps convert excess cholesterol to bile acids. However, these enzymes are also abundant in the brain, adipose tissue, lung, and other tissues. It should be noted that the expression of these enzymes at protein levels is different from the enzymes at the RNA level, which should be considered when researching them.
27-HC has initially been identified as an intrinsic LXR ligand in the field of nuclear receptors, enhancing the performance in a dose- dependent manner (for both LXRa and LXR) [77]. Also, experts in the vascular system demonstrated that 27-HC is a competitor inhibitor of ER. It impedes ER-dependent nitric oxide (NO) production and vascu- lature NO biosynthesis expression in vascular endothelium, associated with decreased vascular recovery upon injuries sustained and additional injuries development of atherosclerotic plaques [55,78]. When re- searchers investigated the possible impact of 27-HC on ERs in different types of cells, in bovine aortic endothelial cells, they discovered that 27- HC inhibited ER transactivation despite in Caco-2 (human colon
cancer cell line) cells and HepG2 promoting pro-estrogenic function. Furthermore, it has been found that 27-HC modifies the configuration of ERa in a manner distinct from E2 interaction with ERa, implying that 27- HC is a SERM [55]. Soon after discovering 27-HC as a SERM, consid- erable research on the effects of 27-HC on the pathology of different diseases, including obesity, Alzheimer’s disease, osteoporosis, cardio- vascular disorders, and many malignancies, has now been reported [79].
5. 27-hydroxycholesterol in health and disease and its role in inflammation
The overwhelming majority of circulatory 27-HC is linked to HDL and LDL [47]. In association with aging, the circulatory concentrations of 27-HC are increased (notably beyond the age of 30) and therefore are assumed to be mainly derived through extrahepatic origins [56,80,81]. Compared to plasma concentrations of 27-HC, their quantity in atherosclerotic plaques is orders of magnitude higher, attaining milli- molar levels in forming foam cells and atherosclerotic lesions[56]. Together with 27-HC, its biosynthetic component, CYP27A1, is common in atherosclerotic plaques, both in endothelial cells and macrophages [48]. The quantity of 27-HC detected in lesions is increased in propor- tionate to the disease severity and the number of macrophages [82,83]. While most 27-HC is esterified in the circulation and atherosclerotic lesions, a significant amount is intact [48,64].
The most prevalent oxysterol in the circulatory system is 27-HC, and plasma concentrations of 27-HC have been significantly related to the quantity of cholesterol in atherosclerotic plaques and the degree of cardiovascular disorders [84,85]. In both rats and humans, females have lower circulating levels of 27-HC than men, which is most probably due to E2 and ER activation of CYPB1 expression [58,59]. Studies in animals disclose how lipid status affects 27-HC material in body tissue, mimicking the interrelations among a circulatory concentration of cholesterol as well as 27-HC in humans.
Oxysterols may have a function in a range of biological processes, according to the results. Emerging pieces of evidence suggest that 27-HC has a broad antiviral and immunomodulatory effect on the human im- mune system [13-15]. Inflammatory processes and lipid metabolism are both influenced by the lipid molecule 27-HC, which is found in the cell membrane [86]. Patients with CYP27A1 gene mutations accumulate cholesterol in peripheral macrophages, highlighting the need of con- verting cholesterol to 27-HC for appropriate cholesterol efflux from peripheral organs [87]. It has been demonstrated that 27-HC counter- acted estrogen’s protective effects on the cardiovascular system in mice [55].
According to research, 27-HC lowers cholesterol levels preventing the synthesis of 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMG-CR) and sterol regulatory element-binding protein-1a (SREBP-1a) [88]. Additionally, it has been demonstrated that 27-HC increases the risk of developing atherosclerosis by activating endothelial cells and mono- cytes/macrophages predominantly through nuclear receptors like ER- or LXR [15,89]. Despite having a reduced potency, 27-HC recapitulated many of the genomic effects of estradiol in ER-positive breast cancer cell types [90]. Additionally, 27-HC has been connected to the development and spread of certain cancers [16]. Together, these findings suggest that 27-HC may have physiological functions that vary depending on the cell and tissue in which it is found, and as a result, it should be appropriately regarded as a possible endogenous SERM.27-HC is a lipid molecule that participates in the metabolism of lipids, cell development, and inflam- matory processes [86]. According to reports, 27-HC inhibits the pro- duction of sterol regulatory element-binding protein-1a (SREBP-1a) and 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMG-CR), lowering cholesterol concentration [88]. Oxysterols act as an intrinsic SERM, increasing the performance of ER positive breast cancer cells. Moreover, 27-HC has been shown to promote atherosclerosis through stimulating monocytes/macrophages and endothelial cells primarily through nu- clear receptors, such as ER-& or LXR [15,89]. It fosters the emigration of
monocytes and C-C chemokine receptor 5 (CCR5)+ T cells, which also contributes to T helper type 1 (Th1) predominance through increasing chemokine manufacturing capacity, promoting the monocytes polari- zation into a proinflammatory subcategory, and influencing the distinction of dendritic cells (DCs) derived from monocytes [91,92]. Furthermore, 27-HC increases the expression of CD14 and pattern recognition receptors (PRRs), such as Toll-like receptor (TLR)-6, and TLR2/6 activator, boosting the reaction to fibroblast-stimulating lip- opeptide-2 (FSL-2), and lipopolysaccharide (LPS), a TLR4 activator [93,94]. According to these findings, 27-HC modulates inflammatory reactions through various methods. Oxysterols are known to be impor- tant regulators of inflammatory response because they cause mono- cytes/macrophages to express inflammatory markers [95-97]. 27-HC enhances the transition of CCR5-expressing monocytic cells and T lymphocytes and stimulates the number of compounds engaged in multiple pathological conditions, such as Tumor necrosis factor-alpha (TNF-a) and C-X-C Motif Chemokine Ligand 8 (CXCL8), and upregulat Major histocompatibility complex (MHC) I and II molecules and PRRs, thus enhancing immune reactions to pathogen-associated molecular patterns [95,98]. The above data support the hypothesis that 27-HC drives macrophages/monocytes toward an immunomodulating state.
It has been established that 27-HC causes or exacerbates inflamma- tory response [99]. In the presence of hypercholesterolemia, an increasedin 27-HC by subcutaneous administration results in increased macrophage infiltration [99]. The proinflammatory impacts of 27-HC appear to be attributable to enhanced inflammatory marker transcrip- tion. 27-HC has been shown to increase the release of C-C Motif Che- mokine Ligand 2 (CCL2) and CCR5 ligands, including CCL4 and CCL3, boosting the emigration of T cells and monocytic cells that display CCR5 [99]. 27-HC significantly promotes the levels of TNF-a, CXCL8, and matrix metalloproteinase-9 (MMP-9) via monocytes/macrophages, and also the overexpression of PRRs modulates the inflammatory response in reaction to damage-associated molecular patterns [99].
6. 27-hydroxycholesterol and cancer development
Many epidemiologic investigations have found a link between low blood cholesterol concentration and the usage of statins, or cholesterol- lowering medicines, with a decreased risk of cancer [48-51], while others argue that there is no link. it has been indicated that reduced concentration and statin usage might promote tumorigenesis [17]. As earlier mentioned, 27-HC has become one of the primary connections linking cholesterol and obesity; hence, 27-HC is most likely the one tied to malignancy and tumorigenesis (Table 1). Increased levels of 27-HC in tumors, which are linked to lower expression of the 27-HC-catabolizing enzyme CYP7B1, have been associated with a poor survival rate in pa- tients [19]. Even after taking into account age, tumor size, nodal status, and peri-operative medication, low CYP7B1 expression is still linked to a poor overall result [19]. Thus, 27-HC is a non-estrogen, locally modu- lated, non-aromatized ER ligand that promotes the development of ER- positive cancers such as breast cancer, and it is prevalent in the micro- environment of tumors. Initially, 27-HC was identified as a pharmaco- logical modulator of the influence of diet with high cholesterol on the formation of breast cancer[20,26]. This type of oxysterols has even been correlated with endocrine tolerance of breast cancer since 27-HC treatment increases the proliferation of MCF7 cells (tamoxifen-resis- tant) to comparable levels to E2 or tamoxifen [20]. It should be noted that clinical analyses can have different endpoints than pre-clinical studies. Hence, many studies, including clinical trials, must be carried out to determine the precise role of 27-HC in cancer. However, in this section, we will go through the pre-clinical and clinical studies con- ducted on the involvement of 27-HC in various malignancies.
6.1. Breast cancer
Breast cancer seems to be the most common cancer in women despite
| Cancer | Study setting | Mechanism | Description | Ref |
|---|---|---|---|---|
| Breast cancer Breast cancer Breast cancer | Phase II clinical (breast cancer patients) Clinical (postmenopausal patients) Clinical (41 participants) | ER modulator Stimulation of ER 1, 25(OH) 2 D inhibition of CYP27A1 | CYP27A1 was expressed in various types of cancer overexpressed in tumors with high stages, ER- negative, and basal-like subtypes. Elevated CYP27A1 activity was associated with prolonged recurrence- free longevity and survival rates. Notably, the protective impact of elevated CYP27A1 on ER- positive breast cancer appeared to be restricted to women over the age of 50. These findings indicate a relationship between CYP27A1 and breast cancer pathogenesis and outcome. They suggest that statin effectiveness in lowering blood lipids does not clearly translate to anti-proliferative actions in malignancies. CYP27A1 was significantly elevated in fewer than one-third of malignancies. High CYP27A1 activity was more common among high tumors that lacked hormone expression and activity and were more prominent in size. In postmenopausal individuals with ER positive breast cancer, CYP27A1 showed considerable promise as a predictor of highly malignant behavior and eventual lethal disease. 27-HC, 25-hydroxyvitamin D (25OHD), and 1, 25 (OH) 2 D levels were evaluated in the serum samples of 29 breast cancer patients before and after treatment with low-dose or high-dose vitamin D in the time between biopsy and surgery. Research findings indicate that vitamin D administration can reduce circulatory 27-HC in patients with breast cancer, most probably through inhibiting CYP27A1. This proposes a novel and other mechanisms through which vitamin D can decrease ER positive breast cancer development, albeit further research is necessary to confirm this. | [108] [118] [239] |
| Breast cancer Breast cancer | Clinical (invasive breast cancer and female control participants) Clinical (benign breast tumor, premenopausal, and postmenopausal patients) | LXR and ER₿ ER and LXR ligand | More CYP7B1-positive patients were PR-positive, and a more significant percentage of ER-ß positive individuals were Bcl-2 lesser than ER-negative subjects. Apart from statistically meaningful variation by LXR-ß status in the subcategory of women perimenopausal at blood sampling, the results of this study found little scientific proof of heterogeneity in correlations among circulating 27- HC and risk of breast cancer through tumor cell expression of CYP27A1, CYP7B1, LXR-ß, and ER. In aggressive breast cancer tissues with positive ERs, there was an increased likelihood of 27-HC and a decreased risk of CYP7B1. These findings suggest that the concentrations of 27-HC and CYP7B1 in breast cancer tissues might be employed as novel molecular indicators for breast cancer prognosis. | [120] [121] |
| Breast cancer Breast cancer | In vivo (ovariectomized and MMTV- PyMT mice) In vivo (Female mice) and in vitro (4 T1 and Met1 and RAW 264.7 cells) | ER and LXR ligand ER and LXR ligand | The impacts of cholesterol on cancer pathophysiology depended on its converting to 27- HC by the CYP27A1, which CYP27A1 antagonists inhibited. CYP27A1 expression levels in human breast cancer tissues are linked with the tumor stage. Both cancer cells and tumor-associated macrophages expressed significant quantities of the enzyme in high-grade malignancies. As a result, reducing circulatory cholesterol levels or interfering with its conversion to 27-HC might have been effective for preventing and/or treating breast cancer. Significantly, 27-HC-induced EVs produced primary PMNs enhanced tumorigenesis and dissemination in two separate syngeneic models, indicating a possible role for 27-HC-induced EVs in tumorigenesis. Tumor cells, macrophages, and PMNs all took up EVs from PMNs, but just not T cells. Because EVs did not affect cancer progression, their pro-tumor activities are probably conducted via associations with myeloid cells. | [20] [115] |
| Breast cancer | In vivo (C57BL/6, and Tcrd tm1/mom /J (TCRD -/-) mice) and in vitro (E0771, Met1 cells) | Myeloid cell function and increased numbers of PMNs and yo T cells, and decreased cytotoxic CD8 + T cells within tumors and metastatic lesions | In relevant tumor experimental animals, CYP27A1 deletion or suppression greatly decreased metastasis. The strong anti-metastasis activities of 27-HC needed myeloid immune cell activity, and it was discovered that this oxysterol boosts the frequency of PMNs and -T cells in distant metastatic locations. 27-HC's pro- (continued on next | [119] |
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| Cancer | Study setting | Mechanism | Description | Ref |
|---|---|---|---|---|
| Breast cancer Breast cancer Breast cancer Breast cancer Breast cancer Breast cancer | In vivo (C57BL/6, BALB/C, OT-I, OT-II, LysMCre, and CYP27A1 fl/fl mice) and in vitro (E0771, E0771-OVA, EL4 and E. G7-OVA, 4 T1-luc cells) In vitro (MCF7 and T47D cells) In vitro (MCF7 and T47D cells) In vitro (MCF-7, MDA-MB-231, and HEK293) In vitro (MCF-7, T-47D, and MB-231) In vitro (HMEC, and HUVECs) | Impairing T cell expansion and cytotoxic function through macrophages in an LXR-dependent manner Activation of STAT-3 signaling by RECK downregulating via ROS EMT and increase the expression of the MMP9 through activation of STAT-3 ER Estrogenic activity and mTOR pathway STAT3 acetylation | metastatic activities need both polymorphonuclear neutrophils and T-yo cells, and 27-HC therapy reduces the amount of cytotoxic CD8 + T cells. As a result of its activities on -T cells and PMNs, 27-HC acts as a physiological modulator of hypercholesterolemia's metastasis consequences. Various oxysterols and LXR ligands demonstrated significant influences on T cell proliferation. Furthermore, their capacity to stimulate the LXR gene transcription ABCA1 was linked to their inhibitory activity T cell growth. Intriguingly, the enzyme implicated in 27-HC production, CYP27A1, is overexpressed in myeloid cells, implying that 27-HC might well have significant autocrine or paracrine operations in these cells, a theory endorsed mainly through the discovery that breast cancer metastasis was diminished in mice with a specialized myeloid knockout of CYP27A1. Notably, inhibiting CYP27A1 decreased metastatic growth and increased the effectiveness of the checkpoint antagonist anti-PD- L1. These findings imply that modulating the CYP27A1 axis in myeloid cells might have therapeutic potential and enhance the respondents' immunological treatments in breast cancer. The formation of cellular ROS induced by 27-HC was shown to significantly enhance MMP9 expression and improve the invasive capacity of MCF7 and T47D cells in this investigation. 27-HC reduced the protein and mRNA expression of RECK in MCF7 and T47D cells in a time- and dose-dependent fashion. Moreover, RECK upregulation inhibited 27-HC- induced metastasis in MCF7 cells. RECK upregulation significantly reduced the increase of p-STAT-3 produced by 27-HC. The findings demonstrated that 27-HC-induced DNA methylation through ROS downregulated RECK, stimulating the STAT-3 upregulation. RECK may be a potential target for modulating the impact of 27-HC on breast cancer. This research reveals that 27-HC might promote EMT and boost MMP9 at mRNA level and active form. Meanwhile, they discovered 27-HC active signal transduction and STAT-3 stimulator in ER-positive cells, but not ER signaling stimulation. The findings indicated significantly higher rates of 27-HC in exosomes derived from an ER positive (MCF-7) compared to exosomes derived from an ER- (MDA-MB-231) as well as other control exosomes (HEK293) and human panel data serum. The exosomal oxysterol pattern did not match the intracellular oxysterol patterns in the source cells; cytoplasmic 27-HC was reduced in ER positive MCF-7 cells but elevated in MDA-MB-231 cells. As a result, exosome characterization in cancer cells may give additional material with diagnosis potential. Once cells are subjected to oxysterols in fetal bovine serum-supplemented media, 7-KC but not 27 HC reduced doxorubicin toxicity in MCF-7 cells, and the P-glycoprotein antagonist verapamil reversed the reduced toxicity. 7-KC enhanced P-glycoprotein mRNA and protein levels in MCF-7 cells. Fulvestrant and ER knockdown restored the 7-KC-suppressed doxorubicin deposition. 7-KC activated the ER significantly more efficiently in a yeast reporter test than 27-HC. Antagonists of PI3K, Akt, and mTOR might revert 7-KC-reduced doxorubicin accumulation. The estrogenic actions of 7-KC and 27- HC are critical in activating P-glycoprotein in breast cancer cells. 27-HC caused EndMT in HMEC-1 and HUVECs, and EndMT accelerated EMT and breast cancer cell migration, according to this investigation. STAT3 knockdown reduced EndMT in HUVECs and emigration in breast cancer cells triggered by 27-HC, according to an examination of the fundamental biological mechanisms. | [100] [117] [22] [114] [246] [247] |
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| Cancer | Study setting | Mechanism | Description | Ref |
|---|---|---|---|---|
| Breast cancer | In vitro (HUVECs) | 14-3-3n/GSK-3B/ß-catenin complex | According to the findings of this research, 27-HC causes oxidative stress in HUVECs. It stimulates the p38 biochemical pathway, blocking the interaction of 4-3-3/GSK-3B/ ß-catenin, increasing the development of free ß-catenin and nuclear translocation, and eventually triggering EndMT. These results suggest that 14-3-3n is required for associations between the p38 kinase and the GSK-36/ B-catenin complexes and functions as an adapter to relay the upstream kinase signal to the downstream signal facilitating EndMT breast cancer cell migration. | [248] |
| Breast cancer | In vitro (MCF-7 and MDA-MB 231) | ERa and LXR and DNA methylation | PTDSS2, MIR613, IDO1, THRA, distorted in (DTYN), and mesoderm inducer early reaction 1, family member 3 were the genes that found significant DNA hypermethylation once ER-positive cells were treated with 27-HC. Furthermore, they discovered that 27- HC inhibits the DNMT3B-Era link in MCF-7 cells. This study found that 27-HC causes aberrant DNA methylation alterations on the promoters of a group of genes via modulating the ERa and DNMT3B complexes, influencing medication reactions and breast tumor progression. | [249] |
| Breast cancer Breast cancer | In vitro (MCF and MDA-MB-231) In vitro (SKBR3 and MDA-MB-231) | ERß, IGF, and EGF axes ER | These findings indicate that 27-HC increases breast tumor growth through ER-xin ER a-positive breast cancer cells. In contrast, ER-ß regulates emigration and invasions in both ER-apositive and negative cell lines. The suppression of the insulin-like growth factor receptor inhibited the effects of cholesterol on TNBC proliferation and migration. The treatment of SKBR3, MDA-MB-231, and MDA- MB-468 with 27-HC increased cell proliferation that G15, a selective GPER inhibitor, prevented this receptor as a potential 27-HC target. Binding experiments demonstrated that 27-HC is a new ligand for GPER. | [240] [10] |
| Breast cancer Prostate cancer | In vitro (MCF7, MDA-MB-231) In vitro (RWPE-1, LNCaP, PC3 cells) | ER by disrupting constitutive p53 signaling ER₿ | The magnitude toward which 27-HC influences cellular proliferation in the MCF7 ER-positive breast cancer cell line was investigated using the tumor suppressor protein p53. MCF7 cells exposed to 27-HC also was related to higher levels of the E3 ubiquitin- protein ligase MDM2 and lower levels of p53. The present findings revealed that incubating LNCaP and PC3 cells with 27-HC boosted cell growth considerably. They further show that the ER antagonist ICI 182,780 (fulvestrant) dramatically inhibited 27-HC-induced cell growth, demonstrating that ERs are involved in reproduction. Notably, after incubating prostate cancer cells with 27-HC, ER levels and ER were dramatically raised to a lesser degree. Additionally, 27-HC-induced propagation is inhibited in the context of the ER-specific antagonist, PHTPP. | [250] [136] |
| Prostate cancer Prostate cancer Colon cancer | In vivo and In vitro (PC3, 22RV1, and LNCaP, and DU145 cells) In silico Clinical | Inhibition of IL6-JAK- STAT3 Signaling CYP27A1 – | In vitro and in vivo 27-HC therapy of STAT3-activated DU145 prostate cancer inhibited STAT3 activity and delayed tumor development. In a broad group of human metastatic castrate-resistant prostate tumors and an invasive prostate cancer subgroup, IL6-JAK- STAT expression level was positively linked with the CYP27A1 expression of genes. Research showed that treatment of prostate cancer cells with 27-HC, an enzymatic component of CYP27A1, decreased cell cholesterol composition in prostate cancer cell lines by impairing SREBP two stimulation and decreased expression of low-density lipoprotein receptor expression. Individuals with circulation 27-HC under the first quartile had a 24% greater risk of adenomas and an 89% greater risk of progressed adenomas than those with circulatory 27-HC, which is above the fourth quartile. | [141] [122] [178] |
| Colon cancer | Clinical (women and men) and in vitro (CaCo-2 cells) | Stimulation of Akt signaling | A constant rise in 27-HC in colorectal cancer volume was seen as matched to tumor-adjacent tissue, but only in later stages of development (TNM stage III). This oxysterol significantly increased pro- inflammatory interleukins 6 and 8, monocyte | [193] |
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| Table 1 (continued) | ||||
|---|---|---|---|---|
| Cancer | Study setting | Mechanism | Description | Ref |
| Colon cancer Gastric cancer | In vitro (Caco2 and SW620) In vitro (HGC-27) | ER and LXR LXR | chemoattractant protein-1, vascular endothelial growth factor, and matrix metalloproteinases 2 and 9. All of these compounds, which have the potential to promote cancer development, seemed to be reliant on a net stimulation of Akt signaling provided through supra-physiological levels of 27-HC. According to this study, 27-HC reduces the phosphorylated and activated form of AKT, a molecule important in cell cycle progression, protein synthesis, and cellular survival. It was also discovered that 27-HC boosted cellular migration in a scratch experiment. 27-HC reduced the epithelial marker E- cadherin while not affecting the mesenchymal marker N-cadherin. Finally, these findings suggest that 27-HC administration causes an increase in cellular emigration via a decrease in reproduction. The concentrations of 24(R/S), 25-EC, and 27-HC in human gastric tumor tissues and malignant gastric juice were considerably higher than those in neighboring normal mucosal tissues and gastric juice from healthy patients. LXRØ-siRNA reduced cell proliferation caused by 27-HC while increasing cell proliferation restriction induced by 24(R/S), 25-EC. Both 24(R/S), 25-EC, and 27-HC significantly hindered HGC-27 cell emigration, which was reduced by co-transfection of cells with LXRa-siRNA and LXRØ-siRNA, although not by either LXRa-siRNA or LXRB-siRNA separately. Finally, the accumulation of 24(R/S), 25-EC, and 27-HC in human gastric tumor tissues may play a crucial role in developing gastric cancer. | [191] [194] |
| Glioblastoma Ovarian cancer Endometrial cancer | In vitro (U251 and U118 MG cells) In vivo In vitro (Ishikawa, RL95, MFE 280 cells) | – ER and LXR ER, and LXR | The current study found that 27-HC increased the proliferation, EMT, colony formation, emigration, and invading of U251 and U118 MG glioma cells. In U251 and U118 MG cell lines, 27-HC administration was likewise related to an increase in the production of glioblastoma-initiating cells. In the current investigation, 27-HC increased the expression of pMAPK, pmTOR, pAKT, p70S6K, and YKL40 in glioblastoma cells. According to the present study, upregulated CYP27A1, the enzyme that catalyzes 27-HC biosynthesis, was related to shorter PFS. In contrast, high expression of CYP7B1, the enzyme that catalyzes 27-HC metabolism, was correlated with elevated PFS. 27-HC, on the other hand, inhibited the cellular growth of numerous ovarian cancer cell lines in an LXR-dependent way. In all stages of endometrial cancer, expression of LXRs (NR1H3, LXR; NR1H2, LXR) and enzymes necessary for the production (CYP27A1) or degradation (CYP7B1) of 27-HC was found. In Ishikawa, RL95, and MFE 280 cells, incubation with 27-HC or GW3965 enhanced transcription through LXRE. 27-HC selectively triggered ER-dependent transcription in Ishikawa cells and increased Ishikawa and RL95 cell growth. 27-HC did not affect cell reproduction in MFE 280 cells, whereas specific targeting of LXR with GW3965 dramatically decreased cell growth. | [228] [212] [219] |
| Lung adenocarcinoma | In vivo (Cyp27A1 +/- mice) and in vitro (A549, H1975, and THP-1 cells) | Phosphorylation of AKT and NF-KB p65, and promoted the expression of PPIB | Cyp27A1 knockdown inhibits the growth and penetration of cholesterol-induced LAC cells. Cyp7B1 knockdown, on the other hand, increased the impact of cholesterol on LAC cell growth and penetration. In addition, Cyp27A1 deletion significantly decreased elevated cholesterol-induced LAC metastases in vivo. Research into the mechanisms revealed that exposing LAC cells to 27-hydroxycholesterol stimulated the phosphorylation of AKT and NF-KB p65 and the production of PPIB. However, 27-HC increased FGF2 and IL-6 production, which aided in the production of snail and vimentin. | [156] |
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| Cancer | Study setting | Mechanism | Description | Ref |
|---|---|---|---|---|
| Lung adenocarcinoma Hepatocellular carcinoma Thyroid cancer Adrenocortical cancer Melanoma Melanoma | In vitro (A549, NCI-H1299, THP-1 cells) In vivo (BALB/c nude mice) and in vitro (HepG2 cell) Clinical (BTT, PTC, and advanced thyroid cancers, which include PDTC/ ATC) Clinical (ACC patients and healthy individuals), in vivo, and in vitro (H295R cell) In vivo (CYP27A1 -/-mice) In vivo (BALB/c-nu/nu female mice), and in vitro (A375 and HEK 293) | Interaction between NFATc1 and phosphorylated STAT3 Activated GRP75 LXR Mitotane action ER-a, AKT, and MAPK signaling AKT -308/309 phosphorylation | The findings revealed that conditioned medium from lung adenocarcinoma cells co-cultured with macrophages increased osteoclast development, which 27-HC aided. In a coimmunoprecipitation test, 27-HC enhanced the association between NFATc1 and phosphorylated STAT3. The chromatin immunoprecipitation experiment revealed that pSTAT3 could bind to the cFos promoter, cFos can attach to the NFATc1 promoter, and both pSTAT3 and NFATc1 might connect to the Oscar promoter, which 27-HC expanded. This research revealed that via increasing oxidative stress signaling, 27-HC stimulated the GRP75. On the one hand, GRP75 altered the redox balance by controlling ROS production and the antioxidant system's performance by changing the concentrations of MMP, NRF2, HO-1, and NQO1. GRP75, on the other hand, altered the metabolic remodeling mechanism via modulating critical components (HIF-1a, p-Akt, and c-myc) and glucose absorption, allowing hepatocellular carcinoma cells to proliferate in an unfavorable microenvironment. Individuals with highly aggressive tumors (high-risk PTC and PDTC/ATC) had lower LDL cholesterol and apolipoprotein B levels in their bloodstream. These modifications were linked to more extraordinary expression of the thyroid's LDL receptor, while 3- hydroxy-3-methylglutaryl-CoA reductase and 25HC 7-a-hydroxylase were downregulated, resulting in an intratumoral rise in the 27-HC metabolite. According to the result of this research, cholesterol and intratumoral deposition of 27-HC boost the aggression-related phase of PTC. As among oxysterols found in mitotane-treated cells, 27-HC, lanosterol, and lathosterol cholesterol substrates were abundant. H295R cell therapy with only one equal micromolar dose of 27-HC had similar cytotoxic activity. In vivo, the mitotane-dependent substantial rise in 27-HC was verified in the plasma of adrenocortical patients who are receiving the medication. The findings demonstrated that a high-cholesterol diet caused a metabolic imbalance and accelerated melanoma development via 27-HC. Further research discovered that 27-HC boosted melanoma cell proliferation by activating the ERa and triggering the AKT and MAPK signaling pathways. DHCR24 was shown to be upregulated in melanoma patients, whereas knocking it down stopped melanoma cells in the S phase and significantly reduced proliferation and metastasis. The recent research also showed that DHCR24 increases the propagation of melanoma stem-like cell types by stimulating Rap1/AKT activation, increasing cellular 27-HC levels. This study also confirmed that CYP27A1 and 27-HC injection both led to the generation of melanoma stem-like cells and vemurafenib tolerance via AKT-308/309 phosphorylation. | [164] [205] [225] [173] [168] [171] |
the progress in detection and intervention; also, breast cancer is a sig- nificant cause of cancer-related death [10]. Increased cholesterol is a serious health concern for the initiation and relapse of breast cancer, whereas cholesterol-lowering medicines, including statins, are corre- lated with a favorable prognosis [100]. In mouse models, cholesterol was found to promote breast tumor progression, and the pro-metastatic actions of cholesterol were attributed to its main metabolite, 27-HC. 27- HC was recently discovered as the first endogenous SERM exhibiting an adjuvant effect on ER positive breast cancer cells (Fig. 1), as well as inhibitory activity in cardiovascular disease models [19,20,55]. 27-HC promotes the proliferation of ER positive MCF7 cell line; nevertheless, estradiol-induced proliferation was decreased upon co-treatment with
escalating 27-HC levels, indicating the possibility of a dual function [90].
27-HC promoted tumor growth via ER stimulation in preclinical studies and cell line models, while the injection of 27-HC decreased estradiol-driven proliferation [101]. In animal studies, higher 27-HC was related to illness development [19,20]. In one prospective trial performed on breast cancer patients, aromatase antagonist therapy resulted in a substantial rise in 27-HC but not with tamoxifen therapy [102]. DL and colleagues [103] studied pre-diagnosis circulatory 27-HC, as well as the risk of breast cancer. They found an inverse connection between circulatory 27-HC and the risk of breast cancer in post- menopausal women with no substantial heterogeneity across ER status
CH
A
A
Stromal cells
Cholesterol
27-OH Cholesterol (27HC)
Cancer cells
27HC
ER
LXR
Cholesterol elimination
Mitogenic program
ABCA1
IDOL
ABCG1
in cancer. When estrogen levels are physiologic (i.e., at premenopausal levels) and the quantity of 27-HC produced from cholesterol is low under normal circumstances, ER function would be sustained, resulting in improved vasoprotection [55]. In contrast, the vascular function of ER would be suppressed, leading to a loss of protection, when the level of 27-HC is higher relative to that of estrogen, such as during the post- menopausal period or as a result of hypercholesterolemia. Until they reach menopause, women are more protected against cardiovascular disease than men are, according to this model.
It is unlikely that 27-HC affects ER activity in premenopausal women due to its poor affinity for ER, but it may do so in postmenopausal women or in the pathophysiological condition of hypercholesteremia. 27-HC may have a significant effect on ER signaling [55,101]. Tamox- ifen, a SERM, is notable for increasing bone mineral density (BMD) in postmenopausal women while antagonistic to ER and decreasing BMD in premenopausal women [104,105]. In vivo investigations are thus necessary to characterize these activities since similar context- dependent agonist and antagonist activities would be anticipated in
studies of the action of 27-HC.
In this regard, Umetani et al. [55] discovered that 27-HC directly antagonizes the transcriptional and non-transcriptional actions of ERs in vascular endothelium and smooth muscle cells, resulting in a loss of the cardioprotective effects of estrogen in mice and rat models. Their find- ings imply a mechanism through which decreasing circulating levels of estrogens in the context of hypercholesterolemia, atherosclerosis, or both may raise the risk of heart disease in postmenopausal women, a situation that may be especially significant. In addition, the identified processes may contribute to the failure of hormone replacement therapy (HRT) in older women as a cardioprotective treatment. As in the case of postmenopausal women who have difficulties (such as atherosclerosis) with increased serum cholesterol and 27-HC, these phenomena may also manifest themselves in breast cancer patients, resulting in elevated levels of 27-HC; thus blocking the preventive effects of estrogen [106]. Despite the fact that a major amount of 27-HC in circulation and tissues is esterified, hypercholesterolemia can increase 27-HC levels in the aorta to the extent that ER function could be altered [106]. Endogenous
estrogen levels are decreased significantly in postmenopausal women, but the risk of ER-positive breast cancer remains high, and synthetic SERM-based therapies are often ineffective, despite the fact that these therapies lose their effectiveness due to processes that are ER-dependent [107]. Due to the fact that cholesterol is a risk factor for the progression of breast cancer, the potential actions of 27-HC on ER-positive breast cancer have been bolded.
Despite a considerable body of experimental data indicating a function for 27-HC in pathogenic mechanisms of breast cancer, it is unclear whether variations in serum and/or intratumoral concentrations of CYP27A1 or 27-HC impact clinical breast cancer cell pathophysiology and patient prognosis [108]. Furthermore, the quantity of 27-HC in ER positive breast cancer cells was shown to be greater than in normal breast tissue, which was linked to a consequent reduction in the activity of the CYP7B1. This enzyme catalyzes the hydrolyze of 27-HC in breast cancer [108]. There is mounting evidence that extracellular vesicles (EVs), particularly exosomes, play a role in cholesterol and lipid equi- librium regulation [109-111]. Under hypercholesterolemic circum- stances, cholesterol could be trapped in EVs, whereas statins can suppress EV secretion [112,113]. Surprisingly, 27-HC may also be found in EVs [114]. Nevertheless, it is unclear whether hormonal and in- termediates govern EV release. Given the significance of oxysterols, including 27-HC in frameworks of cholesterol metabolism, the probable function of EVs in cholesterol balance, and cancer-promoting functions of both EVs and 27-HC, Baek et al. [115] investigated whether 27-HC controls the secretion of EV and discovered an innovative pathway through which cholesterol supports the progression of breast cancer.
By means of the stimulation of the signal transducer and activator of the transcription 3 (STAT3) signaling pathway, 27-HC induces the expression of MMP9, triggers the epithelial-mesenchymal transition (EMT), and enhances the proliferation and metastasis of breast cancer cells [116]. 27-HC can cause oxidative stress in breast cancer cells, resulting in the production of reactive oxygen species (ROS) and acti- vation of the STAT3 signaling pathway. The modulation of STAT-3 or the prevention of ROS production by 27-HC inhibits the vascular endothelial growth factor (VEGF) activation and vasculature formation [117]. The method by which ROS trigger STAT-3 signaling, on the other hand, is mainly unexplored. In a study carried out by Shen and col- leagues, breast cancer cell lines were exposed to 27-HC to explore the effect of Reversion Inducing Cysteine Rich Protein With Kazal Motifs (RECK) on STAT3 signaling mediated by ROS [117]. Researchers discovered that 27-HC increased MMP9 expression and the aggressive capacity of T47D and MCF7 cells by inducing cellular ROS generation. 27-HC reduced the protein and mRNA concentrations of RECK in MCF7 and T47D cultures in a time- and dose-dependent manner. The reduction in RECK expression in MCF7 cells was driven through 27-HC-induced DNA methylation in response to ROS. The activity of MMP9, along with mRNA levels, was increased when RECK was knocked out, boosting MCF7 cell metastasis. According to the results of Shen et al. [117], RECK knockdown enhanced the proportion of p-STAT3 in MCF7 cells, but its upregulation prevented 27-HC-induced metastasis in MCF7 cells. A rise in p-STAT3 produced by 27-HC was further attenuated by RECK over- expression. These findings demonstrate that DNA methylation (induced by 27-HC) by ROS decreased RECK, leading to the promotion of the STAT3 signaling pathway.
These unique findings have enhanced interest in addressing choles- terol biosynthesis in breast cancer and have added CYP27A1 to the list of therapeutic targets for curing ER positive breast cancer. The lack of sensitive tests to quantify the amounts of 27-HC by minimal amounts of materials, including minimal clinical cancer tissues, particular target drugs, and molecular markers for personalized medicine, are among the barriers to translating these intriguing animal model findings into pharmacological interventions. It is currently unknown how 27-HC concentrations in the tumor microenvironment influence the phase of breast cancer development and patient longevity. Kimbung and col- leagues [118] used immunohistochemistry to evaluate CYP27A1
expression in 2 distinct Swedish population-based prospective patient cohorts with intrusive primary breast cancer to discover relevant cor- relations among tumor pathophysiological processes and menopausal conditions and breast cancer outcome in connection to the intratumoral expression of CYP27A1. The overexpression of CYP27A1 was more common in tumors of large size and those with high grades lacking hormonal expression. In postmenopausal individuals with ER positive breast cancer, CYP27A1 holds significant promise as a biomarker of a highly malignant fatal disease. [118]. Future research should examine whether the advantages of long-term hormonal treatment and cholesterol-lowering medicine in breast cancer are influenced by CYP27A1 overexpression.
Raised 27-HC enhances metastatic load and its effects on initial tumor development. Surprisingly, the pro-metastatic actions of 27-HC do not seem to require ER but rather to be stimulated by LXRs. How- ever, synthetic LXR agonists were shown to drive breast cancer cell metastasis, although less successfully than 27-HC. As a result, it was plausible that, in conjunction with activating LXR, 27-HC activated other targets that contribute to the aggressive phenotype. In this context, Baek and colleagues [119] discovered that an isocaloric diet rich in cholesterol alone was sufficient to enhance metastasis in numerous pre- clinical models of breast cancer, clearly confirming cholesterol as a causal factor in metastasis. This effect was correlated with increasing populations of T cells and polymorphonuclear neutrophils (PMNs) and reduced cytotoxic CD8+T cells throughout cancerous and metastatic areas. It might be attributable to the impacts of 27-HC on myeloid cell function [119]. Recent studies indicate that interference with the gen- eration and/or action of 27-HC and cholesterol in subjects with breast cancer and probably other solid tumors may have therapeutic relevance.
In summary, these findings found that intratumoral 27-HC enhances the proliferation of breast cancer cells, as well as their penetration and migration. Nevertheless, the connection between 27-HC and tumor- associated macrophages (TAMs) in breast cancer is unknown. Shi and colleagues [21] discovered that CYP27A1 was expressed at a signifi- cantly higher rate in THP1 (monocytic leukemia cell line)-derived macrophages and THP1 monocytes than in breast cancer cells and that the promoter of CYP7B1 was highly methylated in breast cancer cells [21]. Furthermore, THP-1 monocytes and mouse bone marrow cells are converted into alternatively activated macrophages (M2) after co- culture with breast cancer cells or exposure to exosomes secreted from breast cancer cells [21]. The production of 27-HC in M2 macrophages was significantly higher than in M0 and classical macrophage (M1) phenotypes. 27-HC boosted ER positive cancer cell growth and enhanced the recruiting of monocytes (CCR2- and CCR5-expressing) by causing macrophages to produce numerous chemokines, such as CCL2, CCL3, and CCL4 [21]. These results show that hypermethylation of CYP7B1 and monocyte recruiting significantly lead to the accumulation of 27-HC in breast cancer, the interplay between macrophages and 27- HC, and the promotion of tumor progression. These investigations, taken collectively, are the first of their sort on 27-HC in healthcare sit- uations. Although they cast doubt on the final involvement of 27-HC in breast cancer, they do necessitate more tests and investigations to un- derstand the function and molecular mechanisms underlying 27-HC in the pathogenesis of breast cancer.
Finally, based on a clinical study conducted by Cornet et al. [120], they discovered minimal relationships between tumor marker status and epidemiological features of breast cancer. Furthermore, according to their findings, the link between circulating 27-HC and the risk of breast cancer is unaffected by tumor expression of CYP27A1, LXR, CYP7B1, and ER. In another clinical investigation, malignant breast tumor tissues with positive ER had a greater prevalence of 27-HC and a lower inci- dence of CYP7B1 [121]. Current findings suggested that 27-HC and CYP7B1 levels in breast cancer tissues might be employed as novel biochemical indicators for prognosis.
On the other hand, some studies on 27-HC and breast cancer came to the opposite conclusion. Kimbung and colleagues discovered that a
higher intra-tumoral concentration of CYP27A1 was linked to greater recurrence-free and overall survival of patients with breast cancer [108]. These findings may not be in direct conflict with those obtained by the same group later on, which suggested an inverse relationship between CYP27A1 and recurrence-free and overall survival parameters, but only in postmenopausal women with large breast carcinomas and high dedifferentiation grades [118].
6.2. Prostate cancer
Prostate cancer is a highly aggressive cancer in males and causes a high mortality rate [122]. While the etiology of prostate cancer is un- determined, extensive epidemiologic research has demonstrated that high circulatory levels of cholesterol are associated with an increased incidence of high-grade malignant tumors [123-125]. Moreover, pros- tate cancer cells and those from different malignancies have also been shown to harbor higher amounts of cholesterol than healthy cells [126,127]. As a result, rising cholesterol concentrations may impact prostate cancer advancement by supplying a critical component of cellular membranes to developing cells. According to one current the- ory, raising cellular cholesterol within mitochondrial membranes makes cells tolerant to various chemotherapeutic drugs [128].
Prostate cancer has also been linked to ER communication; the iso- form of ER and a reduced amount of ER are present in prostate stromal and epithelial cells [129,130]. In the setting of prostate cancer, ERa is deemed to be pro-proliferative, whereas ER is believed to be anti- proliferative [131-133]. Nonetheless, ERß inducers have not been demonstrated to possess therapeutic potential in the treatment of pros- tate cancer, so there is a scientific gap relating to the involvement of ER in prostate cancer[134]. Furthermore, the concentration of 27-HC in plasma is raised with age, particularly in men [57]. Men also have increased baseline plasma concentrations of 27-HC versus women [57].
Furthermore, whereas people with hypercholesterolemia are at higher risk of prostate cancer, they even have elevated blood 27-HC concentrations [124,135]. Determining the involvement of 27-HC in prostate cancer is crucial because it may disclose the underlying pro- cesses accountable for tumor onset and development. 27-HC is a SERM that has been shown to attach to and control the function of the ER [90]. 27-HC concentrations are greater in hypercholesterolemic males and older men, both of whom are at increased risk of developing prostate cancer [136]. Considering that elevated concentrations of 27-HC are linked to prostate cancer cases and that 27-HC modifies ER signaling, a pathway involved in prostate cancer progression, it is critical to explore the function of 27-HC in the sense of prostate cancer. Additional research into the function of 27-HC in prostate cancer might result in the development of innovative therapeutic options in addition to those already in the industry. In one investigation, Raza and colleagues [136] discovered that incubating LNCaP and PC3 cells with 27-HC boosted cellular proliferation considerably. They also found that fulvestrant (as an ER inhibitor) significantly decreased cell growth induced by 27-HC, demonstrating that ERs perform a significant function in proliferation.
Interestingly, after incubating prostate cancer cells with 27-HC, ERß concentrations were increased considerably [136]. Moreover, 27- HC-induced propagation is inhibited in the context of the ERß specific antagonist, Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]-pyrimidin- 3-yl]phenol (PHTPP). Overall, these findings reveal that 27-HC, when activated by ER, has a negative influence on prostate cancer cell lines and that dysfunctional concentrations of 27-HC can cause or worsen prostate cancer by acting on ERB.
It is not astounding that blockers of 3-Hydroxy-3-Methylglutaryl- CoA Reductase (HMGCR) prevent cholesterol synthesis and decrease serum cholesterol while inhibiting prostate cancer growth in-vitro are linked to lower prostate cancer cell growth treated with surgical pros- tatectomy or radiation [137,138]. Despite such promising results, it is noteworthy that not all studies have linked hypercholesterolemia to an increased incidence of prostate cancer [139]. Similarly, the results of
statin therapy are not universally hopeful in establishing a connection with prostate cancer risk and/or development, as a number of studies failed to attribute statin usage to a lower the probability of prostate cancer progression [139,140]. Notably, high cholesterol and statin usage impact blood cholesterol levels. It is unclear if these alterations influence intra-tumoral cholesterol. Consequently, despite reflecting the scientific possibility that cholesterol accelerates prostate tumor growth, despite vague epidemiological evidence, it is important to know the underlying pathways that prostate cancer cells use to control intracel- lular cholesterol.
The interleukin 6 (IL-6)- Janus tyrosine kinase (JAK)-STAT3 mechanism forms secreted IL-6 ligands that activate IL-6 receptors, which then phosphorylate JAK and STAT3 [141]. Furthermore, IL- 6-JAK-STAT3 is a recognized transduction pathway in prostate cancer [142,143]. Numerous reports have indicated that hindering this pathway could also regulate prostate tumorigenesis in preclinical animal models. Studies performed on human metastatic castrate-resistant prostate cancer (mCRPC) cells, as well as specimens obtained from fast autopsies and biopsies, demonstrate the role of stimulated IL-6 re- ceptors and p-STAT3 in bone metastasis in comparison to visceral and lymph node metastasis, confirming the significance of this pathway and pharmacological properties in prostate cancer [141,144,145]. Dambal and colleagues [141] investigated the mechanism through which 27-HC displays anti-prostate tumor effects. Since cholesterol is an element of membrane microspheres termed as lipid rafts, determining the location of receptors and directing cellular signaling, the researchers anticipated that 27-HC might disrupt lipid rafts, utilizing the IL-6-JAK-STAT3 complex as a model due to its importance in prostate cancer. 27-HC therapy dramatically reduced cholesterol accumulation in the cellular membrane, as demonstrated by single-molecule scanning of DU145 prostate cancer cells. Furthermore, in-vitro and in-vivo administration of 27-HC to STAT3-activated DU145 prostate cancer cells led to the inhi- bition of STAT3 activity and a delay in cancer development. 27-HC suppressed phosphorylation of STAT3 (mediated by IL-6) in non- STAT3-activated DU145 prostate cancer cells [141]. 27-HC inhibited nuclear translocation, DNA accessibility to STAT3, and STAT3 homo- dimerization at specific gene promoters. Once 27-HC and STAT3 tar- geted drugs were combined, the proliferation and migration effects were synchronous and synergistic [141]. In a broad group of human meta- static castrate-resistant tumor shrinkage and invasive PC subtypes, the expression levels of the IL-6-JAK-STAT complex were positively asso- ciated with CYP27A1 gene expression [141]. This shows that STAT3 stimulation might be a tolerance strategy for malignant prostate cancer cells still expressing CYP27A1. In conclusion, the recent research iden- tified a critical mechanism through which 27-HC reduces prostate can- cer via destroying lipid rafts and inhibiting STAT3 activity. The mentioned findings imply that 27-HC modulation of intracellular cholesterol may hinder IL-6-JAK-STAT signaling and might even coop- erate with STAT3-targeted medications.
In a survey conducted by Alfaqih and co-workers [122], they used a bioinformatic method to assess genetic traits whose expression is dys- regulated in prostate cancer. They discovered that the expression of CYP27A1 was significantly dysregulated in prostate cancer, especially in comparison to benign prostate tissue [146]. A mix of genetic, bioinfor- matics and pharmaceutical methods were applied to assess the role of CYP27A1 and 27-HC in cholesterol balance in prostate cancer [122]. Furthermore, dysregulation of CYP27A1 expression and its metabolite, 27-HC, have been demonstrated to alter the pathobiology of prostate cancer. These findings, taken collectively, emphasize the promising clinical benefit of maintaining cholesterol equilibrium in prostate cancer to treat or prevent the illness. As a result, 27-HC might perform a variety of functions in promoting prostate cancer, justifying the use of cholesterol-lowering therapy for this condition.
However, it should be noted some studies clearly reported that 27- HC generated both stimulatory and inhibitory signals in terms of cell proliferation, EMT, cell invasion, migration, and metastasis. ERa, in
particular, was shown to be pro-proliferative, whereas ERß and LXRs were found to be anti-oncogenic and anti-proliferative in prostate cancer [147]. Besides, the expression of CYP7B1 in tumor tissue was consid- erably reduced in a study carried out on prostate cancer tissues, which was likely due to hypomethylation of its promoter region. This event implies that 27-HC may has have lower rate of metabolic and/or catabolismin prostate cancer [148]. This meant that a conclusive declaration failed to be made about the development and preventive role of 27-HC in prostate cancer.Lung Cancer.
It has also been demonstrated that high cholesterol increases the likelihood of developing lung cancer [149,150]. In lung adenocarci- noma, cholesterol lowers the responsiveness of platinum-based chemo- therapies, such as L-acetyl-carnitine (LAC) [151]. Fluvastatin, an antagonist of HMGCR, inhibits LAC bone metastasis [152]. Tumor dissemination is the primary reason for LAC’s high death rate and poor outcome [153]. However, the significance of cholesterol metabolism in LAC metastasis is still opaque. Earlier studies have shown a cholesterol byproduct, 4-cholesten-3-one, inhibits LAC dissemination via modu- lating the trafficking of hypoxia-inducible factor 1-alpha (HIF-1x), caveolin-1, and high-mobility group box 1 (HMGB1), although 25- HC increases LAC proliferation and migration and is invasive in both LXR-dependent and LXR-independent ways [154,155]. The contra- dicting actions of cholesterol compounds are most probably responsible for the imprecise relationship between elevated cholesterol and a poor prognosis of LAC. It is critical to leverage elements to understand the influence of cholesterol on LAC propagation and dissemination. Although 27-HC has been shown to increase osteoclast formation in the LAC milieu, it is unclear if 27-HC is implicated in LAC dissemination and whether 27-HC relates elevated cholesterol to LAC dissemination. Li et al. [156] reported that cholesterol increased cell invasion and metastasis of LAC in-vitro and in-vivo. The knockdown process of Cyp27A1 decreased the impact of cholesterol on cell growth and inva- sion. Correspondingly, in-vivo depletion of Cyp27A1 substantially inhibited the increased serum diet-induced LAC spreading. These find- ings suggest that 27-HC appears to be essential for the promotion of high-cholesterol LAC metastasis in the diet. It has been demonstrated that 27-HC triggered the phosphorylation of Akt and Nuclear factor kappa B (NF-KB) and the production of peptidylprolyl isomerase B (PPIB) [156]. The suppression of PPIB decreased the generation of vimentin and snail produced through 27-HC. The above finding revealed that 27-HC was linked to LAC metastasis through boosting PPIB tran- scription. Osteolytic bone metastasis is common in the late stages of lung cancer [157]. Metastatic cancer cells can influence bone rebuilding through how osteoclasts and osteoblasts communicate [158]. Once cancer cells move to bone tissues, various cell types are attracted into the milieu, aiding in the production of cytokines, immunological reactions, osteoblast, and osteoclast development [159]. Immune cells might play a significant function in the interaction between cancer and skeletal functioning cells [159]. Cancer cells can interfere with immune cells, driving them to produce mediators, which accelerate osteoclast forma- tion. 27-HC may cause macrophages to secrete interleukin-8 (IL-8) and TNF-a [160,161]. TNF-& is a potent stimulator of osteoclastogenesis [162]. Independently of the receptor activator of NF-KB (RANK) ligand (RANKL) axis, IL-8 might induce osteoclast formation [163]. Hence, Zhang and colleagues [164] investigated the impact of 27-HC on oste- oclast formation in lung tumor cells and macrophage co-culture plat- forms. The results showed that conditioning media from lung adenocarcinoma cells co-cultured with macrophages increased osteo- clast development, which was aided by 27-HC [164]. According to further research, a conditioned medium decreased microRNA 139 (miR- 139) expression while promoting cFos expression. The luciferase re- porter test indicated that cFos is a primary target of miR-139. The chromatin immunoprecipitation test revealed that pSTAT3 might attach to the cFos promoter, cFos may attach to the nuclear factor of activated T cells 1 (NFATc1) promoter, and the both NFATc1 and pSTAT3 might bind to the Oscar promoter, which was expanded by 27-HC but inhibited
by miR-139 [164]. This evidence shows that conditioned media, particularly those containing 27-HC, aided osteoclastogenesis by sup- pressing miR-139 production and stimulating the STAT3/cFos/NFATc1 network.
6.3. Melanoma
Malignant melanoma, which develops from skin mucocutaneous pigment melanocytes, is expected to be prevalent in the United States and Europe [165]. It also has a poor prognosis and a substantial fatality rate [166]. Obesity and type 2 diabetes have been indicated to increase the risk of melanoma [167]. The precise processes underlying such an association are unclear. Tian and colleagues [168] demonstrated the putative links between 27-HC and the progression of melanomas in obese or hypercholesterolemic individuals. Many studies have confirmed the presence of ERs in melanoma [169,170]. The findings showed that hepatocyte-derived 27-HC might stimulate ER in melanoma cells and control the proliferation and differentiation via the AKT and mitogen-activated protein kinase (MAPK) signal transduction pathways. Of note, maintaining the level of 27-HC can slow the advancement of the illness. Overall, the present results indicate a novel treatment approach for the experimental treatment of melanoma. Moreover, Zhong and colleagues [171] discovered that 24-Dehydrocholesterol Reductase (DHCR24) increased melanoma development in xenograft mice. Furthermore, DHCR24 stimulated Rap1 and caused the buildup of 27- HC in melanoma cells [171]. These observations paved the way for targeting DHCR24 as a possible treatment option for metastatic melanoma.
6.4. Adrenocortical carcinoma
Adrenocortical cancer is an uncommon, malignant endocrine cancer frequently linked with hypercortisolism and has a poor outcome [172]. Although cholesterol-lowering drugs were employed in preclinical ani- mal models to cure many forms of cancer [173], the biochemical role of cholesterol intermediates and/or metabolites in adrenocortical cancer development remain largely unknown. Germano et al. [173] found a particular rise of 27-HC in H295R cells confirmed with a mitotane to exert toxic and pro-apoptotic impacts. In their study, the same toxicity effect was found by adding an identical amount of 27-HC instead of the mitotane against H295R cells.
Besides, the main oxysterols were found in H295R cells as well as in the plasma of adrenocortical cancer patients receiving mitotane treat- ment, confirming a significant modulation of steroidogenesis and a unique feature of mitotane action in the rise of 27-HC [173]. In conclusion, they concluded that the cytotoxicity of mitotane against adrenocortical cancer cells is largely due to the elevated intracellular level of 27-HC, and 27-HC appears to be a useful predictor of mitotane activity.
6.5. Colon cancer
Colorectal cancer (CRC) is one of the most frequent types of cancer in women and men, with an estimated prevalence of more than 1.2 million cases annually [174,175]. The condition is a leading cause of cancer- related death and has slightly improved overall survival; the five-year survival rate remains very low at around 55% [174,176]. Because CRC grows gradually over many years and signs typically appear only in the later phases, several CRC emerges at an advanced phase. The five- year survival rate for individuals with metastatic disease becomes less than 10% [174]. Although oxysterol signaling is known to play a func- tion in tumorigenesis, recent research on the main cytochrome P450 implicated in the oxysterol pathway has focused on their transcription in tumors.Swan and colleagues[177] used a well-characterized cohort of CRC to evaluate the expression of cholesterol metabolizing enzymes, including CYP51A1, CYP39A1, CYP46A1, CYP27A1, CYP7B1, CYP8B1,
and CYP2R1 in primary CRC tissue. In this study, the whole patient population and mismatch repairing competent CRC, an oxysterol metabolizing enzyme expression pattern linked to prognosis was discovered.
Many studies have found that oxysterols have a vital function in developing GI malignancy [178]. Colon cancer has been related to an- imal fat oxidation products, such as oxysterols. High expression of Transforming growth factor-beta 1 (TGF-ß1) in fibroblasts and macro- phages, which are prevalent in the cancer microenvironment, is one probable explanation for this impact [179]. Intestinal epithelial cells generally use TGF-ß1 to promote maturation and death. TGF-61 (type I and/or type II receptor) expression is reduced in colon cancer cells [179]. As a result, colon cancer cells are less vulnerable to the growth- regulating actions of TGF-61. Enhanced concentrations of TGF-ß1 are hypothesized to be implicated in the selective removal of malignant cells sensitive to this cytokine’s pro-apoptotic actions, permitting the clonal growth of TGF-01-insensitive tumor tissues by indirect means [180,181]. Consequently, the inhibition of TGF-$1 growth might be disrupted, allowing for unrestrained neurogenesis and transformation. The alteration in the expression of TGF-ß1 has been reported in malig- nancies of the lung, breast, colon, and prostate [182-185]. In the Caco-2 cell line, a combination of oxysterols, including 5, 6-epoxycholesterol (6%), 7-hydroxycholesterol (43%), and 5, 6-epoxycholesterol (32%), triggered apoptosis. It is unclear if circulatory 27-HC is linked to the risk of colon cancer cells. Passarelli and colleagues [178] used liquid chromatography-mass spectrometry (LC-MS) to assess circulatory 27-HC in fasting plasma taken at baseline from patients in the Vitamin D/ Calcium Polyp Protection Experiment, a finished randomized clinical trial. The recent investigation discovered that plasma concentrations of 27-HC affect lipid metabolism and function as a SERM, related to the probability of developing CRC precursor lesions [178]. The magnitude of the relationships found among circulatory 27-HC and the incidence of colorectal adenocarcinoma were typically weak; therefore, these ob- servations are doubtful to have urgent therapeutic use. Molecular research is needed to understand that 27-HC is compatible in the com- plex region of other lipid signal transmissions that are suspected to be CRC biomarkers, particularly eicosanoids and various sphingolipids [186]. LXR activators, both natural and synthetic, that increase reverse cholesterol transfer are also being investigated as potential prospective statin alternatives to prevent cardiovascular diseases [187]. On the other hand, a clinical trial in the early stages of an LXR activator to reduce the incidence of atherosclerosis showed safety problems [188]. Compounds that preferentially stimulate LXR in the small bowel have been discovered as prospective CRC therapeutic options, although they are still to be tested in clinical trials [189,190]. These findings imply that trials of innovative therapeutics that contribute to higher serum con- centrations of 27-HC should also evaluate possible prolonged effects on CRC progression.
The involvement of 27-HC in colon cancer cell lines was discovered by Warns and colleagues [191]. They also studied the impact of 27-HC on cellular differentiation by measuring the protein Schlafen Family Member 12 (SLFN12). They found that the treatment of SW620 and Caco2 cells with 27-HC reduced cell growth without causing any cyto- toxic effects or apoptosis. Warns and colleagues [206] discovered that 27-HC promoted cellular mobility through a scratched experiment. 27- HC reduced the epithelium signature E-cadherin while not affecting the mesenchymal indicator N-cadherin. Cells must cease replicating before they may move. In sum, these findings suggest that 27-HC administration increases cellular migration while decreasing proliferating.
Furthermore, there is accumulating evidence that 27-HC may initiate and maintain surviving signals in many cell lines [192]. In a nutshell, the potential pathways through which this oxysterol may boost GI cancer cell longevity and intrusiveness were thoroughly examined. The exis- tence of proof that 27-HC is raised in tissues of colon cancer patients and that its availability may be operationally connected to tumor growth
was formerly lacking; hence, the primary goal of this study by Rossin and colleagues [193] was to design and evaluate this issue. The present investigation gives the first comprehensive image of the quantity of 27- HC detected in human CRC as it progresses through the phases of met- astatic diseases. Even though this oxysterol-type molecule seems to accrue progressively from Tumor, Node, Metastasis (TNM) phase I to TNM stage III, it revealed a significant rise in 27-HC relative to the equivalent tumor-adjacent healthy tissue was only evident in stage III CRC. Importantly, LC-MS findings indicate comparatively low levels of other oxysterols than 27-HC in the CRC mass, either of catalytic source, i.e., 24-Hydroxycholesterol (24-HC) and 25-HC, or non-enzymatic origin [193]. The quantity of 27-HC detected in additional CRC speci- mens of varying phases was well within the range of concentrations reported in neighboring normal mucosa specimens. As a result, in the case of human CRC, these data would obviously demonstrate that a buildup of 27-HC occurs at an advanced phase of disease growth. The absence of an additional increase in 27-HC identified in the increasingly limited samples of stage IV CRC is partially explained by the significant dedifferentiation demonstrated by tumor cells at that point, reflecting a virtually total loss of gut characteristics [193]. A putative increase in tumor cell concentrations of this or related oxy-sterols linked to cancer aggressiveness might be crucial for the development and intrusiveness of many types of cancer and should be explored further. Whenever an amount considerably higher than the biological one is attained, as in the intestine, 27-HC has seemed to be capable of completely contributing to even tumorigenesis via provoking and maintaining the upregulation of pro-inflammatory mediators, anti-apoptotic factors, and tissue matrix metalloproteinases. These in-vitro results indicate a function for increased Akt signaling in the latter inflammatory reaction CRC devel- opment and distant metastasis.
6.6. Gastric cancer
Gastric cancer is one of the most frequent malignancies and the second most common cause of cancer-related morbidity worldwide [98,194,195]. More profound knowledge of etiology and the detection of changes in compounds (molecules/metabolites) are involved in forming efficient treatment methods for gastric cancer patients. Oxy- sterols have complex impacts on many GI malignancies. In colon cancer cells, oxysterols have both pro-apoptotic/cytotoxic and pro-cancerous activities [196]. Oxysterols work along with ROS and lipid peroxides to produce metabolic disturbances, repair issues, and DNA damage, resulting in cell gene alterations that contribute to cholangiocarcinoma formation [196,197]. The concentrations of 24(R/S), 25-epoxycholes- terol, and 27-HC in human gastric cancer tissues are considerably higher than those in surrounding normal stomach mucosal tissues. Guo and colleagues [194] used LC-MS to determine the amounts of sulfated, oxysterols, and cholesterol in human gastric cancer tissues, surrounding healthy tissues of the mucosal layer, malignant gastric juice, and gastric juice taken from gastric juice in healthy individuals. Studies indicated that the concentrations of 27-HC, 24(R/S), and 25-epoxycholesterol in human gastric cancer tissues and malignant digestive juices were much higher than in neighboring healthy mucosal tissues and digestive juices from healthy individuals. Human gastric cancer tissues had lower amounts of 25-HC3S and a lower proportion of 25-HC3S/25-HC than GI mucosal tissue, which might be connected to the drastically lower Sul- photransferase 2A1 (SULT2A1) transcription in gastric cancer tissue [194]. Gastric cancer propagation was inhibited by 24(R/S), 25-epoxy- cholesterol, and 27-HC, although not by LXRa-siRNA therapy. HGC-27 cell migration was significantly decreased through both 24(R/S), 25- epoxycholesterol, and 27-HC, mitigated by co-transfection of cells with LXRß-siRNA or LXRa-siRNA, although not by LXRØ-siRNA or LXRa- siRNA separately. Finally, the accumulation of 25-epoxycholesterol of 24(R/S) and 27-HC in gastric cancer tissues may perform a function in gastric cancer development.
6.7. Hepatocellular carcinoma
Because 27-HC is selectively toxic to many cells, such as HCC cells, certain HCC cells (almost 30%) exhibit a specific cholesterol acyltransferase-2-dependent metabolic mechanism, which protects them from cytotoxic effects induced by 27-HC throughout the progres- sion of HCC [198]. Nevertheless, as the tumor stage proceeds, there is an increase in the deposition of 27-HC in HCC tissues, implying that a unique, undiscovered mechanism is utilized to expedite HCC cell longevity in an unlivable milieu [199,200]. According to the latest research, while 27-HC produced oxidative injury, an enhancement in ROS constant level, which 27-HC created, activated survival-promoting signaling [201,202]. Furthermore, a large body of data, such as recent latest investigations, suggest that 27-HC plays a significant role in developing lung cancer, breast cancer, and other tumors [20,22,203,204]. Jane et al. [211] discovered that long-term adminis- tration of 27-HC made HCC cells resistant to 27-HC, which induced cytotoxicity and induced multidrug resistance (MDR) .. Based on the molecular processes, 27-HC stimulated glucose-regulated protein 75 (GRP75) by increasing oxidative stress signaling. On the one side, GRP75 changed redox homeostasis by controlling ROS generation and the function of the antioxidant defense system, allowing HCC cells to endure the cytotoxicity triggered by 27-HC and chemotherapeutics [205]. GRP75, on the other side, altered the metabolic remodeling mechanism, allowing HCC cell proliferation in the presence of chemicals mentioned above in unfavorable settings. Prolonged exposure to a higher concentration of 27-HC is a unique feature of the HCC microen- vironment as a result of the liver tissue specificity [205]. The recent research discovered a putative strategy implicated in MDR associated with prolonged contact to and a “switch”-like component, GRP75. Most significantly, targeting GRP75 switched the activity of 27-HC from tumor progression to HCC cytotoxicity, implying another novel approach to HCC treatment.
6.8. Ovarian cancer
Although the links between ovarian cancer and obesity are most likely complicated and multivariate, it is notable because raised circu- latory cholesterol is frequently detected in obese individuals, and there is a clear link between increased plasma LDL and lowers progression- free survival (PFS) and disease-specific survival (DSS) [206,207]. Pa- tients receiving cholesterol-lowering medications showed significantly enhanced PFS and DSS [208-210]. These findings imply that cholesterol may have a vital function in the pathogenesis of ovarian cancer. That cholesterol could significantly contribute to the connections between obesity and poor prognosis. The relevance of 27-HC in ovarian cancer is unknown. Anti-estrogens have been proven to be very beneficial only in endometrioid ovarian cancer and not in high-grade malignancies, which are more prevalent [211]. As a result, He et al. [212] launched a set of experiments to determine the possible functions of 27-HC in the advancement of ovarian cancer. They discovered that the upregulation of CYP27A1 was linked to lower PFS, whereas the overexpressed CYP7B1, an enzyme catalyzing 27-HC degradation, was linked to enhanced PFS. 27-HC, on the other hand, inhibited the cellular growth of numerous cell lines of ovarian cancer in an LXR-dependent manner [212]. Cancer cells from mice treated with 27-HC showed changes in the myeloid cell components, and cells from the bone marrow stem lineage are accountable for the effects in CYP27A1+/- animals. Although the suppression of CYP27A1 or immune checkpoint inhibitors did not sub- stantially affect cancer growth, their conjunction did, suggesting this pathway as a potential therapeutic.
In conclusion, while increasing dietary cholesterol or therapy with exogenous 27-HC slows the course of ovarian cancers, their basal quantities in normocholesterolemic mice are probably adequate to sustain cancer formation. Ovarian cancer, on the other hand, does not grow in animals missing CYP27A1, which most possibly results in
abnormal maturation and/or activity of myeloid-derived suppressor cells (MDSCs). This creates the possibility of employing immunotherapy to target this pathway. Preclinical findings indicating tumor suscepti- bility to programmed death ligand-1 (PD-L1) by the CYP27A1 antago- nist significantly support this strategy [100].
6.9. Endometrial cancer
Endometrial cancer is a gynecologic tumor and the fourth most frequent cancer in women in industrialized nations, with occurrence growing in parallel with the prevalence of obesity and overweight [213]. Endometrial cancer is linked to obesity, which is a major risk factor. It is vital in contributing to a higher risk of mortality as a result of increased estrogen exposure, which promotes the probability of abnormal endometrial propagation [214]. Obesity is also linked to a poor metabolic parameter, which is thought to raise the risk of endo- metrial cancer on its own [215]. A new meta-analysis found a link be- tween increased cholesterol intake and endometrial cancer risk [216]. Obesity, in particular, puts individuals at the possibility of having a high cholesterol profile. Cholesterol compounds, including 27-HC, have accelerated tumorigenesis and metastasis in breast cancer research, implying a possible molecular relationship between obesity and endo- metrial cancer risk. It has been demonstrated that LXRs may work as a potential anti-cancer target based primarily on research findings in breast cancer, and the LXR-selective receptor activation bib901317 and GW3965 have also been shown to reduce the propagation of LXR- expressing breast cancer cell lines [217,218]. Given that specific LXR agonists have anti-proliferative impacts, these findings imply that the proliferating consequences of 27-HC might well be communicated through endometrial cancer and that the relative expression of LXR or endometrial cancer variants might characterize the ligand’s influence [217]. Obesity and metabolic disorders are both associated with a higher likelihood of experiencing pre-malignant and malignant endometrial diseases, although it is unknown if 27-HC influences endometrial cancer vulnerability [214]. Gibson and co-workers [219] examined the expression of enzymes responsible for the biosynthetic CYP27A1, break- down CYP7B1 of 27-HC, and the cognate receptors LXR-x and LXR-ß in phase I endometrial adenocarcinomas and endometrial controls (post- menopausal). Overall, these findings indicate that approaches aimed at limiting 27-HC access via changes in lifestyle, lipid-lowering medicine including statins, or innovative drug discovery that address 27-HC production (CYP27A1 inhibitors) might well be efficacious in decreasing endometrial propagation in women at high risk of getting endometrial cancer. These data imply that impairment in cholesterol metabolism and abnormal input to 27-HC might affect endometrial tumorigenesis.
6.10. Thyroid carcinoma
Various observational studies have been conducted to assess the relationship between high-fat diets, dyslipidemia, and cancer [220- 222]. This association is currently unclear in thyroid cancer. At the same time, recent research during the last decade shows that fat mass pro- portion, high cholesterol, and obesity might be associated with a heightened risk of thyroid cancer [223,224]. The consequences of li- poprotein metabolism and 27-HC on thyroid cancer development are currently unknown. In this context, Revilla et al. [225] investigated the correlation between intratumoral concentrations of 27-HC, cholesterol, and the aggressiveness of thyroid cancer. Subjects with more advanced diseases had lower amounts of apolipoprotein B and LDL in their blood. These modifications were coupled with a rise in thyroid LDL receptor expression, but 7-a-hydroxylase and 3-hydroxy-3-methylglutaryl-CoA reductase was significantly suppressed, with an intratumoral elevation in the 27-HC compound [225].
Additionally, whereas LDL enhanced reproduction in thyroid cellular models, such as CAL-62 and Nthy-ori 3.1, its cellular mobility was
considerably elevated only in anaplastic thyroid cancer cells. They find that cholesterol and intratumoral 27-HC formation increase the invasive aggressiveness of papillary thyroid cancer. In thyroid cancers with a poor prognosis, manipulating cholesterol biosynthesis might be a po- tential treatment option.
6.11. Glioblastoma
One of the most common primary aggressive brain tumors in adults is glioblastoma [226,227]. 27-HC dramatically increases the development of breast cancer in animal models of breast cancer, propagation, and metastasis. Nevertheless, towards state of the art, no studies investigated the impact of 27-HC on glioblastoma. As a result, Liu and colleagues [228] conducted research to discover the precise involvement of 27-HC in glioblastoma. They found that 27-HC induced proliferation, EMT, colony formation, emigration, and invading in U251 and U118 MG glioblastoma cells. 27-HC administration was also linked with an in- crease in glioblastoma-initiating cells’ development in U118 MG and U251cell lines [228]. Furthermore, elevated concentrations of 27-HC in glioblastoma tissues were linked to a poor prognosis in sufferers. Finally, 27-HC, the main cholesterol byproduct, could have a crucial function in developing glioblastoma.
Recently, 27-HC metabolism was explored in neuroblastoma cells (SH-SY5Y cell line) which simultaneously expressed CYP27A1 and CYP7B1, indicating that such cells might convert 27-HC into 7a-hy- droxy-3-oxo-4-cholestenoic acid [229]. However, these findings help explain the source of the net flow of 7a-hydroxy-3-oxo-4-cholestenoic acid from the brain to the circulatory reported in humans, the tumor origin; SH-SY5Y cells might influence the phenotypic, as well as sensi- tivity to pathophysiological stimuli. The synthesis of 27-HC in-situ via brain cells cannot be ruled out. Elevated amounts of 27-HC, for instance, were found in the brains of dead Alzheimer’s patients [230]. Moreover, recent research found that high cerebral concentrations of 27-HC are linked to sterol buildup in mice missing the Abcg1/Abcg4 transporters [231]. Gilardi and colleagues [232] discovered that fresh astrocytes expressed various sterol hydroxylases and could absorb exogenous 27- HC. They discovered that LXR was expressed predominantly by micro- glia and astrocytes. Regardless of the resemblance, Gilardi and col- leagues [232] found cell-specific responses towards LXR stimulation of predictable and unpredictable (particularly CYP27A1) target genes. Transactivation of the upstream CYP27A1 promoter in transfected as- trocytes parallels the rise in mRNA and protein concentrations in pre- treated astrocytes. The astrocyte-specific overexpression of CYP27A1 might be attributed to differences in transcriptional co-activator expression. Considering the significance of astrocytes in brain homeo- stasis, a decrease in CYP27 activity in such cells might disrupt important astrocyte functions ranging from the processing and distribution of cholesterol to neurons to the secretion of signal transduction.
7. 27-hydroxycholesterol based therapy and potential diagnostic biomarker
As previously stated, elevated amounts of 27-HC cause dysfunctions and malignancies. As a result, reducing 27-HC concentrations is considered to be an effective way to treat or protect against these dis- orders. The CYP7B1 and CYP27A1 were involved in the biosynthesis of 27-HC. CYP27A1 is affected by various stimuli, including hormones and cytokines [107]. Furthermore, hydroxysteroid sulfotransferase lowers cholesterol and oxysterol concentrations, especially 27-HC [233,234]. Even though the transcription and activity of this enzyme have been linked to malignancies, such as the liver, stomach, and skin cancer, the enzymes are not unique to 27-HC, and their biological relevance remains unknown [234,235]. In terms of pharmaceutical treatments to lower 27- HC concentrations, certain Cytochrome P450 enzyme blockers and statins decrease 27-HC concentration. However, since they are not specific to 27-HC, it is difficult to determine the significant effect of
lowering 27-HC on the illness [108]. While the systemic suppression of CYP27A1 (particularly in the liver) changes bile acid and cholesterol biogenesis, prospective inhibitors of CYP27A1 might reduce 27-HC concentrations in the circulation, thereby preventing the disease [236]. Although some Food and Drug Administration (FDA)-approved treatments, including cyclosporine and many aromatase antagonists, showed solid inhibitory activity on CYP27A1, more targeted therapy against CYP27A1 might well be helpful [18].
In animal studies, knocking down the 27-HC-producing enzyme CYP27A1 decreases cancer incidence and the volume of ERpositive breast cancer tumors in murine models [20]. Despite increasing evi- dence that 27-HC plays a vital role in activating ER positive breast cancer, there is no treatment to target the 27-HC biosynthetic pathway. However, it has been speculated that the potential benefit of statin drugs in the development of cancer may be directly attributed to the effect of lowering 27-HC synthesis and lowering cholesterol [20]. According to a recent investigation, atorvastatin has been seen to lower serum 27-HC while increasing CYP27A1 expression levels in 42 patients with breast cancer were studied in preliminary research; moreover, the upregula- tion of CYP27A1 in ERpositive breast cancer has been linked to pro- longed recurrence-free and absolute longevity [108]. The above findings highlight the significant role of the 27-HC axis in tumorogenesis and the importance of addressing the 27-HC axis in the treatment of ER positive breast cancer.
CYP27A1 shares 40% of its sequences with CYP27B1, and it likewise possesses 1-a-hydroxylase activities against 25-hydroxyvitamin D (25OHD) [237,238]. Given the similarities between CYP27B1 and CYP27A, Going et al. [239] investigated vitamin D suppression of 27-HC formation via calcitriol-induced inhibition of CYP27A1 expression, revealing a new mechanism for vitamin D to decrease ER positive breast cancer and a potential strategy for targeting the 27-HC pro- duction pathway. In an interventional trial conducted on 29 women with breast cancer, it was shown that augmenting circulation of 25OHD concentrations with nutritional supplements might lower the amount of circulatory 27-HC in most subjects. This experimental study should be confirmed in more substantial studies.
Moreover, Mashat and colleagues [240] developed models to confirm the influence of cholesterol and its derivative, 27-HC, on breast tumor growth, migrations, invasions, and the presence of EMT charac- teristics. The administration of LDL/27-HC boosted Insulin-like growth factor (IGF)-I synthesis and IGF-IR predominance in triple-negative breast cancer (TNBC). They also, in TNBC, discovered that manipu- lating ER with an activator or inhibitor promoted or lowered the con- centrations of epidermal growth factor (EGF) and IGF-I receptors [240]. The suppression of the IGFR prevented cholesterol’s impacts on cell proliferation and migration of TNBC. They discovered that greater levels of ERß were related to higher concentrations of IGF-IR employing microarray expression profiles (METABRIC and TCGA) from metastatic breast cancer [240]. As a result, the current study has found that ER is vital in the impact of LDL/27HC on infiltration, migrations, and EGF and IGF axis. According to the findings of Mashat and colleagues [240], inhibiting ER in TNBC might be an alternate way of decreasing the expression of EGF/IGF signaling and limiting the influence of LDL in patients with breast cancer.
Furthermore, CYP27A1 transcript levels in breast cancercorrelated with tumor stage [19,20]. It is thus feasible to study 27-HC internal and external biomarker features in ERpositive and ER negative breast cancer [241]. Exosomes have lately gained prominence as critical elements of extracellular signaling. Exosomes are tiny extracellular vesicles (usually 30-100 nm) generated via secretory vesicles [242,243]. Exosomes were initially assumed to be of little clinical significance; now, evidence is overwhelming, indicating exosomes are engaged in several tasks, including cancer progression and preparing certain organs for malignant transformation [244]. Exosomes can transport various biological com- ponents containing cancer-causing chemicals, proteins, and RNA [242,243]. Exosomes are frequently released more significantly by
tumor cells than healthy cells [245]. Therefore, in context, Roberg- Larsen and colleagues [119] proposed a unique capillary LC-MS-based technique for preliminary investigations into the existence and amounts of 27-HC in exosomes from diverse ERpositive and ER negative breast cancer cells. Researchers discovered significantly higher quanti- ties of 27-HC in exosomes produced from an ER positive MCF-7 than exosomes originating from an ER negative MDA-MB-231 and other control exosomes [114]. The oxysterol patterns in exosomes did not reflect the oxysterol patterns in the originating cells. Other cancer cells in the control group had varying amounts of cytoplasmic oxysterol. As a result, exosome characterization in tumor cells could also provide additional data with diagnosing potential.
8. Conclusion and future outlook
The identification of 27-HC as an endogenous SERM has prompted much research into the possible functions of this molecule in a variety of diseases, including cancer. The processes through which 27-HC in- fluences cancer development are complicated and multifaceted. Never- theless, based on the findings in animal studies and epidemiological evidence in humans, it appears that 27-HC represents an intermediate metabolite to connect cholesterol and the chance of breast cancer. As a SERM, 27-HC has stimulated or repressed ERs in tissue-specific contexts. 27-HC promotes tumorigenesis from various sources, notably prostate (endocrine-related) and breast cancer. Furthermore, throughout the case of ovarian and prostate cancer, the implications of 27-HC to cancer development appear to be a proportionate result of 27-HC working as an ER inducer along with its function as a cholesterol modulator; also, 27- HC has been demonstrated to stimulate prostate cancer cell proliferation via the ER6, while, the reduction in cellular cholesterol level induced via 27-HC was detrimental to tumorigenesis. Several different studies sug- gest that blocking the enzyme CYP27A1, which produces 27-HC, can minimize cancer formation and increase checkpoint inhibitor effec- tiveness. While some of these studies indicate that 27-HC had a signif- icant role in these malignancies, the findings are still debatable, and further studies are required to fully comprehend the significance of 27- HC in these tumors. A lack of broad clinical trials has created a signifi- cant gap in our understanding of 27-HC and its possible involvement in disorders ranging from obesity to malignancy; therefore, prospective clinical research is critical in bridging similar deficiencies. As the im- pacts of 27-HC in mouse models of several malignancies are revealed, there is a need to develop medicines, such as antagonists agents, to reduce the concentration of 27-HC both in the tumor microenvironment and in cancerous tissue to limit cancer outcomes.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data availability
No data was used for the research described in the article.
Acknowledgment
The authors are grateful to Scientific Research Deanship at King Khalid University, Abha, Saudi Arabia for their financial support through the Large Research Group Project under grant number (RGP.02- 230-43).
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