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.