title: Activators of the farnesoid X receptor negatively regulate androgen glucuronidation in human prostate cancer LNCAP cells.
abstract: Androgens are major regulators of prostate cell growth and physiology. In the human prostate, androgens are inactivated in the form of hydrophilic glucuronide conjugates. These metabolites are formed by the two human UGT2B15 [UGT (UDP-glucuronosyltransferase) 2B15] and UGT2B17 enzymes. The FXR (farnesoid X receptor) is a bile acid sensor controlling hepatic and/or intestinal cholesterol, lipid and glucose metabolism. In the present study, we report the expression of FXR in normal and cancer prostate epithelial cells, and we demonstrate that its activation by chenodeoxycholic acid or GW4064 negatively interferes with the levels of UGT2B15 and UGT2B17 mRNA and protein in prostate cancer LNCaP cells. FXR activation also causes a drastic reduction of androgen glucuronidation in these cells. These results point out activators of FXR as negative regulators of androgen-conjugating UGT expression in the prostate. Finally, the androgen metabolite androsterone, which is also an activator of FXR, dose-dependently reduces the glucuronidation of androgens catalysed by UGT2B15 and UGT2B17 in an FXR-dependent manner in LNCaP cells. In conclusion, the present study identifies for the first time the activators of FXR as important regulators of androgen metabolism in human prostate cancer cells.
authors.affiliation: Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec, QC, Canada G1V 4G2.
authors.forename: Jenny
authors.initials: J
authors.lastname: Kaeding
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bouchaert
authors.forename: Julie
authors.initials: J
authors.lastname: Bélanger
authors.forename: Patrick
authors.initials: P
authors.lastname: Caron
authors.forename: Sarah
authors.initials: S
authors.lastname: Chouinard
authors.forename: Mélanie
authors.initials: M
authors.lastname: Verreault
authors.forename: Olivier
authors.initials: O
authors.lastname: Larouche
authors.forename: Georges
authors.initials: G
authors.lastname: Pelletier
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Alain
authors.initials: A
authors.lastname: Bélanger
authors.forename: Olivier
authors.initials: O
authors.lastname: Barbier
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000738:Androsterone / Q000494:pharmacology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D008297:Male; D015778:Minor Histocompatibility Antigens; D016133:Polymerase Chain Reaction; D011467:Prostate / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000728:Androgens; D000738:Androsterone; D004268:DNA-Binding Proteins; D014453:Glucuronosyltransferase; D015778:Minor Histocompatibility Antigens; D012313:RNA; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014535:Uridine Diphosphate Glucuronic Acid; D000099150:Receptor, Farnesoid X-Activated; C472000:UDP-glucuronosyltransferase 2B15, human; C500513:UGT2B17 protein, human