Dihydrotestosterone (DHT) is regarded as the most potent natural
androgen and is implicated in the development and progression of
castration resistant
prostate cancer (CRPC). Under castrate conditions, DHT is produced from the metabolism of the adrenal
androgen precursors,
DHEA and
androstenedione. Recent studies have shown that the adrenal
steroid 11β-hydroxyandrostenedione (11OHA4) serves as the precursor to the
androgens 11-ketotestosterone (11KT) and
11-ketodihydrotestosterone (11KDHT). In this study we comprehensively assess the androgenic activity of 11KT and 11KDHT. This is the first study, to our knowledge, to show that 11KT and 11KDHT, like T and DHT, are potent and efficacious agonists of the human
androgen receptor (AR) and induced both the expression of representative AR-regulated genes as well as cellular proliferation in the
androgen dependent
prostate cancer cell lines, LNCaP and VCaP. Proteomic analysis revealed that 11KDHT regulated the expression of more AR-regulated
proteins than DHT in VCaP cells, while in vitro conversion assays showed that 11KT and 11KDHT are metabolized at a significantly lower rate in both LNCaP and VCaP cells when compared to T and DHT, respectively. Our findings show that 11KT and 11KDHT are bona fide
androgens capable of inducing
androgen-dependant gene expression and cell growth, and that these
steroids have the potential to remain active longer than T and DHT due to the decreased rate at which they are metabolised. Collectively, our data demonstrates that 11KT and 11KDHT likely play a vital, but overlooked, role in the development and progression of CRPC.