Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer - Abstract

Department of Urology, Roswell Park Cancer Institute, Buffalo, New York. Department of Urology, University at Buffalo, State University of New York, Buffalo, New York; Lineberger Comprehensive Cancer Center; Laboratories for Reproductive Biology, Department of Pediatrics, and Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina; and National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina.

The androgen receptor (AR) mediates the growth of benign and malignant prostate in response to dihydrotestosterone (DHT). In patients undergoing androgen deprivation therapy for prostate cancer, AR drives prostate cancer growth despite low circulating levels of testicular androgen and normal levels of adrenal androgen. In this report, we demonstrate the extent of AR transactivation in the presence of 5α-androstane-3α,17β-diol (androstanediol) in prostate-derived cell lines parallels the bioconversion of androstanediol to DHT. AR transactivation in the presence of androstanediol in prostate cancer cell lines correlated mainly with mRNA and protein levels of 17β-hydroxysteroid dehydrogenase 6 (17β-HSD6), one of several enzymes required for the interconversion of androstanediol to DHT and the inactive metabolite androsterone. Levels of retinol dehydrogenase 5, and dehydrogenase/reductase short-chain dehydrogenase/reductase family member 9, which also convert androstanediol to DHT, were lower than 17β-HSD6 in prostate-derived cell lines and higher in the castration-recurrent human prostate cancer xenograft. Measurements of tissue androstanediol using mass spectrometry demonstrated androstanediol metabolism to DHT and androsterone. Administration of androstanediol dipropionate to castration-recurrent CWR22R tumor-bearing athymic castrated male mice produced a 28-fold increase in intratumoral DHT levels. AR transactivation in prostate cancer cells in the presence of androstanediol resulted from the cell-specific conversion of androstanediol to DHT, and androstanediol increased LAPC-4 cell growth. The ability to convert androstanediol to DHT provides a mechanism for optimal utilization of androgen precursors and catabolites for DHT synthesis.

Written by:
Mohler JL, Titus MA, Bai S, Kennerley BJ, Lih FB, Tomer KB, Wilson EM.   Are you the author?

Reference: Cancer Res. 2011 Feb 15;71(4):1486-96.
doi: 10.1158/0008-5472.CAN-10-1343

PubMed Abstract
PMID: 21303972 Prostate Cancer Section