title: UGT2B17 Expedites Progression of Castration-Resistant Prostate Cancers by Promoting Ligand-Independent AR Signaling.
abstract: Castration-resistant prostate cancer (CRPC) is characterized by a shift in androgen receptor (AR) signaling from androgen-dependent to androgen (ligand)-independent. UDP-glucuronosyltransferase 2B17 (UGT2B17) is a key enzyme that maintains androgen homeostasis by catabolizing AR agonists into inactive forms. Although enhanced UGT2B17 expression by antiandrogens has been reported in androgen-dependent prostate cancer, its roles in regulating AR signaling transformation and CRPC progression remain unknown. In this study, we show that higher UGT2B17 protein expression in prostate tumors is associated with higher Gleason score, metastasis, and CRPC progression. UGT2B17 expression and activity were higher in androgen-independent compared to androgen-dependent cell lines. UGT2B17 stimulated cancer cell proliferation, invasion, and xenograft progression to CRPC after prolonged androgen deprivation. Gene microarray analysis indicated that UGT2B17 suppressed androgen-dependent AR transcriptional activity and enhanced of ligand-independent transcriptional activity at genes associated with cell mitosis. These UGT2B17 actions were mainly mediated by activation of the c-Src kinase. In CRPC tumors, UGT2B17 expression was associated positively with c-Src activation. These results indicate that UGT2B17 expedites CRPC progression by enhancing ligand-independent AR signaling to activate cell mitosis in cancer cells. Cancer Res; 76(22); 6701-11. ©2016 AACR.
authors.affiliation: Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Haolong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Ning
authors.initials: N
authors.lastname: Xie
authors.affiliation: Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Ruiqi
authors.initials: R
authors.lastname: Chen
authors.affiliation: Laboratory of Molecular Pharmacology, CHU de Québec Research Centre, and the Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Verreault
authors.affiliation: Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: Laboratory of Molecular Pharmacology, CHU de Québec Research Centre, and the Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Olivier
authors.initials: O
authors.lastname: Barbier
authors.affiliation: Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada. xdong@prostatecentre.com.
authors.forename: Xuesen
authors.initials: X
authors.lastname: Dong
mesh_terms: D000818:Animals; D018450:Disease Progression; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics*; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D046888:Tissue Array Analysis; D014162:Transfection
chemical_list: D008024:Ligands; D015778:Minor Histocompatibility Antigens; D011944:Receptors, Androgen; D014453:Glucuronosyltransferase; C500513:UGT2B17 protein, human