PMID- 20534728
OWN - NLM
STAT- MEDLINE
DCOM- 20100908
LR  - 20220410
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Linking)
VI  - 151
IP  - 8
DP  - 2010 Aug
TI  - 3beta-hydroxysteroid dehydrogenase is a possible pharmacological target in the 
      treatment of castration-resistant prostate cancer.
PG  - 3514-20
LID - 10.1210/en.2010-0138 [doi]
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 3beta-hydroxysteroid dehydrogenase 
      (3betaHSD) metabolism of Delta(5)-steroids, including dehydroepiandrosterone 
      (DHEA) and Delta(5)-androstenediol (A5diol), to testosterone. In contrast, 
      reports that DHEA and A5diol directly activate the androgen receptor (AR) suggest 
      that 3betaHSD metabolism is not required and that 3betaHSD 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 3betaHSD to 
      androstenedione and testosterone, respectively. Here, we show that DHEA and 
      A5diol induce AR chromatin occupancy and AR-regulated genes. Furthermore, we show 
      that Delta(5)-androgens undergo 3beta-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 3betaHSD. These findings demonstrate that DHEA and 
      A5diol must be metabolized by 3betaHSD to activate AR in these models of CRPC. 
      Furthermore, this work suggests that 3betaHSD may be exploited as a pharmacologic 
      target in the treatment of CRPC.
FAU - Evaul, Kristen
AU  - Evaul K
AD  - Division of Hematology and Oncology, Department of Internal Medicine, University 
      of Texas Southwestern Medical Center, Dallas, Texas 75390-8852, USA.
FAU - Li, Rui
AU  - Li R
FAU - Papari-Zareei, Mahboubeh
AU  - Papari-Zareei M
FAU - Auchus, Richard J
AU  - Auchus RJ
FAU - Sharifi, Nima
AU  - Sharifi N
LA  - eng
GR  - Howard Hughes Medical Institute/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20100609
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (AR protein, human)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Receptors, Androgen)
RN  - 08J2K08A3Y (Dihydrotestosterone)
RN  - 459AG36T1B (Dehydroepiandrosterone)
RN  - EC 1.1.- (17-Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.1.51 (3 (or 17)-beta-hydroxysteroid dehydrogenase)
RN  - L0FPV48Q5R (trilostane)
SB  - IM
MH  - 17-Hydroxysteroid Dehydrogenases/*antagonists & inhibitors/metabolism/physiology
MH  - Antineoplastic Agents/*administration & dosage/pharmacology
MH  - Carcinoma/*drug therapy/genetics/pathology/surgery
MH  - Cell Line, Tumor
MH  - Cell Nucleus/drug effects/metabolism
MH  - Dehydroepiandrosterone/metabolism
MH  - Dihydrotestosterone/administration & dosage/analogs & derivatives/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Drug Delivery Systems
MH  - Drug Evaluation, Preclinical
MH  - Enzyme Inhibitors/administration & dosage/pharmacology
MH  - Humans
MH  - Male
MH  - Models, Biological
MH  - Orchiectomy
MH  - Prostatic Neoplasms/*drug therapy/genetics/pathology/surgery
MH  - Receptors, Androgen/metabolism
MH  - Treatment Failure
EDAT- 2010/06/11 06:00
MHDA- 2010/09/09 06:00
CRDT- 2010/06/11 06:00
PHST- 2010/06/11 06:00 [entrez]
PHST- 2010/06/11 06:00 [pubmed]
PHST- 2010/09/09 06:00 [medline]
AID - en.2010-0138 [pii]
AID - 10.1210/en.2010-0138 [doi]
PST - ppublish
SO  - Endocrinology. 2010 Aug;151(8):3514-20. doi: 10.1210/en.2010-0138. Epub 2010 Jun 
      9.