5α-androstane-3α,17p-diol supports human prostate cancer cell survival and proliferation through androgen receptor-independent signaling pathways: Implication of androgen-independent prostate cancer progression

Androgen and androgen receptor (AR) are involved in growth of normal prostate and development of prostatic diseases including prostate cancer. Androgen deprivation therapy is used for treating advanced prostate cancer. This therapeutic approach focuses on suppressing the accumulation of potent androgens, testosterone and 5α-dihydrotestosterone (5α-DHT), or inactivating the AR. Unfortunately, the majority of patients with prostate cancer eventually advance to androgen-independent states and no longer respond to the therapy. In addition to the potent androgens, 5α-androstane- 3α,17(β-diol (3α-diol), reduced from 5α-DHT through 3α-hydroxysteroid dehydrogenases (3α-HSDs), activated signaling may represent a novel pathway responsible for the progression to androgen-independent prostate cancer. Androgen sensitive human prostate cancer LNCaP cells were used to compare 5α-DHT and 3α-diol activated androgenic effects. In contrast to 5α-DHT, 3α-diol regulated unique patterns of β-catenin and Akt expression as well as Akt phosphorylation in parental and in AR-silenced LNCaP cells. More significantly, 3α-diol, but not 5α-DHT, supported AR-silenced LNCaP celIs and AR negative prostate cancer PC-3 celI proliferation. 3α-diol-activated androgenic effects in prostate cells cannot be attributed to the accumulation of 5α-DHT, since 5α-DHT formation was not detected following 3α-diol administration. Potential accumulation of 3α-diol, as a result of elevated 3α-HSD expression in cancerous prostate, may continue to support prostate cancer growth in the presence of androgen deprivation. Future therapeutic strategies for treating advanced prostate cancer might need to target reductive 3α-HSD to block intraprostatic 3α-diol accumulation.