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
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.
Hoang, David Timothy, "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" (2016). ETD Collection for Thomas Jefferson University. AAI10085656.