Inhibition of Androgen-Independent Growth of Prostate Cancer by siRNA- Mediated Androgen Receptor Gene Silencing; Final rept. 15 Jan 2004-14 Jan 2008

摘要

To determine if AR gene silencing in prostate cancer cells via RNA interference mechanism leads to disruption of androgen-independent progression. We generated a recombinant AAV for long-term expression of a hairpin-structured AR siRNA in vivo. Then we determined the essential role of the androgen receptor in androgen-independent growth of prostate cancer. We demonstrated that knocking down AR expression abolished tumor growth and blocked androgen- independent transition in LNCaP and LAPC-4 cell-derived xenografts. In addition, we observed that AR silencing resulted in a significant decrease of androgen- independent tumor growth in C4-2 cell-derived xenografts in castrated mice. We also demonstrated that knocking down AR expression by systemic delivery of the AAV particle eradicated CWR22RV1 androgen-independent xenograft tumors but not AR-null PC-3 xenograft tumors. We analyzed the mechanisms for AR siRNA-induced cell death and identified the anti-apoptotic proteins SGK1 and Bcl-xL, as the downstream effecters of AR-mediated survival pathway. Most of these results were published (Appendix II-VI).