11-ketodihydrotestosterone and 11-hydroxyandrostenedione

Adrenal C19 steroids, dehydroepiandrostenedione (DHEA(S)) and androstenedione (A4), play a critical role in castration resistant prostate cancer (CRPC) as they are metabolised to dihydrotestosterone (DHT), via testosterone (T), or via the alternate 5α-dione pathway, bypassing T. Adrenal 11OHA4 metabolism in CRPC is, however, unknown. We present a novel pathway for 11OHA4 metabolism in CRPC leading to the production of 11ketoT (11KT) and novel 5α-reduced C19 steroids - 11OH-5α-androstanedione, 11keto-5α-androstanedione, 11OHDHT and 11ketoDHT (11KDHT). The pathway was validated in the androgen-dependent prostate cancer cell line, LNCaP. Androgen receptor (AR) transactivation studies showed that while 11KT and 11OHDHT act as a partial AR agonists, 11KDHT is a full AR agonist exhibiting similar activity to DHT at 1nM. Our data demonstrates that, while 11OHA4 has negligible androgenic activity, its metabolism to 11KT and 11KDHT yields androgenic compounds which may be implicated, together with A4 and DHEA(S), in driving CRPC in the absence of testicular T.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 3-Hydroxysteroid Dehydrogenases; 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Aldo-Keto Reductase Family 1 Member C3; Androgens; Androstenedione; Animals; Biosynthetic Pathways; Cell Line, Tumor; Chromatography, High Pressure Liquid; Estradiol Dehydrogenases; Humans; Hydroxyprostaglandin Dehydrogenases; Hydroxytestosterones; Male; Mass Spectrometry; Membrane Proteins; Molecular Weight; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Testosterone; Transcriptional Activation; Transfection