Therapeutic Targeting of Stat5a/b in Advanced Prostate Cancer: Inhibition of Stat5a/b Suppresses Growth of Prostate Cancer through Mechanisms Dependent and Independent of Androgen Receptor.

摘要

Progression of prostate cancer to the incurable and lethal castrate-resistant stage is accompanied by failure of therapies targeting the androgen receptor (AR) signaling axis, which inhibit AR-dependent proliferation and survival pathways. Signal Transducer and Activator of Transcription 5a/b (Stat5a/b) has previously been identified and validated as a therapeutic target protein in prostate cancer. In this thesis, we demonstrate that Stat5a/b promotes growth of prostate cancer through both AR-independent and AR-dependent mechanisms. Regarding AR-independent mechanisms, we show that genetic knockdown or pharmacological inhibition of AR permits survival of a prostate cancer cell subpopulation which retains sensitivity to Stat5a/b inhibition. Mechanistically, Stat5a/b was found to regulate a component of prostate cancer cell viability independently of AR, and disruption of Stat5a/b signaling induces extensive apoptotic death of androgen-dependent as well as AR signaling-depleted cells. Stat5a/b inhibition also blocked growth of both androgen-dependent and castrate/antiandrogen-resistant prostate cancer xenograft tumors and clinical prostate cancers grown ex vivo. Our results suggest that combination or sequential therapy with antiandrogens and Stat5a/b inhibitors is superior to antiandrogen monotherapy in suppressing growth and viability of advanced prostate cancer in vitro and in vivo. Regarding AR-dependent mechanisms, we show that Stat5a/b protects AR liganded by antiandrogens from proteasomal degradation and physically interacts with AR, potentiating AR signaling in the presence of antiandrogen therapy. Active Stat5a/b enhances nuclear localization of unliganded and antiandrogen-liganded AR, occupancy of AR at an AR-regulated promoter and expression of AR-regulated genes. Both antiandrogen therapy and Stat5a/b genetic knockdown individually increased proteasomal degradation of AR, while combined inhibition of AR and Stat5a/b induced maximal loss of AR protein through the proteasome and suppression of prostate cancer cell growth. In conclusion, our findings suggest that therapeutic targeting of Stat5a/b may provide a dual strategy to inhibit growth and viability of prostate cancer. Blockade of Stat5a/b signaling may present a novel therapeutic strategy to potentially improve efficacy of antiandrogens in primary prostate cancer and bypass continued AR signaling in advanced CRPC after onset of resistance to antiandrogens.