MP55-16 BLOCKING THE INTRACRINE BACK-CONVERSION PATHWAY WITH ABIRATERONE IN PROSTATE CANCER CELLS

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research III1 Apr 2015MP55-16 BLOCKING THE INTRACRINE BACK-CONVERSION PATHWAY WITH ABIRATERONE IN PROSTATE CANCER CELLS Takashi Ando, Itsuhiro Takizawa, Fumio Ishizaki, Keisuke Takeda, Yoshimichi Miyashiro, Noboru Hara, and Tsutomu Nishiyama Takashi AndoTakashi Ando More articles by this author , Itsuhiro TakizawaItsuhiro Takizawa More articles by this author , Fumio IshizakiFumio Ishizaki More articles by this author , Keisuke TakedaKeisuke Takeda More articles by this author , Yoshimichi MiyashiroYoshimichi Miyashiro More articles by this author , Noboru HaraNoboru Hara More articles by this author , and Tsutomu NishiyamaTsutomu Nishiyama More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2059AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In castration-resistant prostate cancer (CRPC), dehydroepiandrosterone (DHEA) is most common precursor of testosterone (T) and dihydrotestosterone (DHT). We reported 5a-androstane-3b,17b-diol (3β-diol), which is inactive androgen metabolized from DHT, can be converted back to DHEA and finally to DHT. In this pathway, 3β-hydroxysteroid dehydrogenase (3β-HSD) is the key enzyme for the conversion from DHEA and epiandrosterone (epiAND) to DHT, and Rui et al. reported abiraterone inhibited 3β-HSD in CRPC. We examined the effect of CYP17 inhibitors on the intracrine back-conversion pathway induced by 3β-diol in prostate cancer cells. METHODS LNCaP cells were incubated in the presence of 3β-diol or DHEA 10nmol/L with or without CYP17 inhibitors (abiraterone, ketoconazole, or orteronel) 10nmol/L. In all experiments, LNCaP cells were incubated without any androgens and CYP17 inhibitors as a control (CTRL). After incubation, PSA levels in the media were determined by enzyme immunoassay, and androgen levels in media were measured by LC-MS/MS. RESULTS By adding DHEA or 3β-diol in media, PSA levels were increased (p = 0.013 and p < 0.001, respectively). 3β-diol highly activated AR about five-times compared to DHEA. Inhibition of PSA secretion by abiraterone, ketoconazole and orteronel was found in the presence of DHEA (p < 0.001, p = 0.002, and p = 0.017, respectively). 3β-diol-induced PSA accumulation in media was inhibited by abiraterone, not ketoconazole or orteronel. By adding 3β-diol in medium, DHEA, androstenediol (A-diol), androstendione (A-dione), T, and DHT levels were increased compared to CTRL. In the media with 3β-diol and abiraterone, A-dione, T, DHT, and 5α-androstanedione (5α-A-dione) levels were decreased, DHEA, 5-diol, and epiAND levels increased compared to 3β-diol only. CONCLUSIONS AR was highly activated by 3β-diol compared to DHEA through the conversion of 3β-diol to DHT by way of epiAND and 5α-A-dione, which abiraterone blocked by inhibiting 3β-HSD. Abiraterone has a potential to inhibit the intracrine back-conversion pathway. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e678-e679 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Takashi Ando More articles by this author Itsuhiro Takizawa More articles by this author Fumio Ishizaki More articles by this author Keisuke Takeda More articles by this author Yoshimichi Miyashiro More articles by this author Noboru Hara More articles by this author Tsutomu Nishiyama More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...