TY - JOUR
T1 - 3β-hydroxysteroid dehydrogenase is a possible pharmacological target in the treatment of castration-resistant prostate cancer
AU - Evaul, Kristen
AU - Li, Rui
AU - Papari-Zareei, Mahboubeh
AU - Auchus, Richard J.
AU - Sharifi, Nima
N1 - Copyright:
Copyright 2010 Elsevier B.V., All rights reserved.
PY - 2010/8
Y1 - 2010/8
N2 - Prostate cancer usually responds to androgen deprivation therapy, although the response in metastatic disease is almost always transient and tumors eventually progress as castration-resistant prostate cancer (CRPC). CRPC continues to be driven by testosterone or dihydrotestosterone from intratumoral metabolism of 19-carbon adrenal steroids from circulation, and/or de novo intratumoral steroidogenesis. Both mechanisms require 3β-hydroxysteroid dehydrogenase (3βHSD) metabolism of Δ5-steroids, including dehydroepiandrosterone (DHEA) and Δ5-androstenediol (A5diol), to testosterone. In contrast, reports that DHEA and A5diol directly activate the androgen receptor (AR) suggest that 3βHSD metabolism is not required and that 3βHSD inhibitors would be ineffective in the treatment of CRPC. We hypothesized that activation of AR in prostate cancer by DHEA and A5diol requires their conversion via 3βHSD to androstenedione and testosterone, respectively. Here, we show that DHEA and A5diol induce AR chromatin occupancy and AR-regulated genes. Furthermore, we show that Δ5-androgens undergo 3β-dehydrogenation in prostate cancer and that induction of AR nuclear translocation, AR chromatin occupancy, transcription of PSA, TMPRSS2, and FKBP5, as well as cell proliferation by DHEA and A5diol, are all blocked by inhibitors of 3βHSD. These findings demonstrate that DHEA and A5diol must be metabolized by 3βHSD to activate AR in these models of CRPC. Furthermore, this work suggests that 3βHSD may be exploited as a pharmacologic target in the treatment of CRPC.
AB - Prostate cancer usually responds to androgen deprivation therapy, although the response in metastatic disease is almost always transient and tumors eventually progress as castration-resistant prostate cancer (CRPC). CRPC continues to be driven by testosterone or dihydrotestosterone from intratumoral metabolism of 19-carbon adrenal steroids from circulation, and/or de novo intratumoral steroidogenesis. Both mechanisms require 3β-hydroxysteroid dehydrogenase (3βHSD) metabolism of Δ5-steroids, including dehydroepiandrosterone (DHEA) and Δ5-androstenediol (A5diol), to testosterone. In contrast, reports that DHEA and A5diol directly activate the androgen receptor (AR) suggest that 3βHSD metabolism is not required and that 3βHSD inhibitors would be ineffective in the treatment of CRPC. We hypothesized that activation of AR in prostate cancer by DHEA and A5diol requires their conversion via 3βHSD to androstenedione and testosterone, respectively. Here, we show that DHEA and A5diol induce AR chromatin occupancy and AR-regulated genes. Furthermore, we show that Δ5-androgens undergo 3β-dehydrogenation in prostate cancer and that induction of AR nuclear translocation, AR chromatin occupancy, transcription of PSA, TMPRSS2, and FKBP5, as well as cell proliferation by DHEA and A5diol, are all blocked by inhibitors of 3βHSD. These findings demonstrate that DHEA and A5diol must be metabolized by 3βHSD to activate AR in these models of CRPC. Furthermore, this work suggests that 3βHSD may be exploited as a pharmacologic target in the treatment of CRPC.
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U2 - 10.1210/en.2010-0138
DO - 10.1210/en.2010-0138
M3 - Article
C2 - 20534728
AN - SCOPUS:77954909020
SN - 0013-7227
VL - 151
SP - 3514
EP - 3520
JO - Endocrinology
JF - Endocrinology
IS - 8
ER -