Adrenal androgens rescue prostatic dihydrotestosterone production and growth of prostate cancer cells after castration.

Abstract Adrenal androgens dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) are potential substrates for intracrine production of testosterone (T) and dihydrotestosterone (DHT), or directly to DHT, by prostate cancer (PCa) cells. Production of DHT from DHEAS and DHEA, and the role of steroid sulfatase (STS), were evaluated ex vivo using fresh human prostate tissue and in vitro using human PCa cell lines. STS was expressed in benign prostate tissue and PCa tissue. DHEAS at a physiological concentration was converted to DHT in prostate tissue and PCa cell lines, which was STS-dependent. DHEAS activation of androgen receptor (AR) and stimulation of PCa cell growth were STS-dependent. DHEA at a physiological concentration was not converted to DHT ex vivo and in vitro , but stimulated in vivo tumor growth of the human PCa cell line, VCaP, in castrated mice. The findings suggest that targeting metabolism of DHEAS and DHEA may enhance androgen deprivation therapy. Highlights • Prostate tissue and prostate cancer cell lines converted DHEAS and DHEA to DHT. • Conversion of DHEAS to DHT depended on steroid sulfatase. • DHEAS and DHEA activated AR and stimulated growth of prostate cancer cell lines. • DHEAS-stimulated growth i n vitro was STS- and AR-dependent. • DHEA sustained growth of prostate cancer cell line VCaP in castrated mice. [ABSTRACT FROM AUTHOR]