The pro-metastatic and survival protein Survivin is robustly overexpressed in carcinomas compared to normal or benign tissue. The imadazolium based small molecule YM155, which was discovered in a chemical library screen of compounds that effectively suppressed the Survivin promoter, induces apoptosis of castration-resistant prostate cancer (CRPC) cells. Despite the current use of YM155 in phase II clinical trials, the mechanisms by which YM155 inhibits the expression of Survivin and kills cancer cells remain unclear. Our laboratory previously reported that the pocket proteins (Rb, p107, p130) suppress Survivin expression by recruiting E2F4 to CDE/CHR promoter elements of the Survivin promoter. Here we studied early signaling responses in a panel of prostate and kidney cancer cell lines and showed that YM155 rapidly decreases the levels of cyclin Ds and activates Rb, preceding the suppression of Survivin expression. We hypothesize that YM155 down-regulates Survivin expression by activating the pocket proteins and promoting their recruitment along with E2F4 to the proximal region of the Survivin promoter. In addition, we provide evidence that the induction of apoptosis by YM155 may be mediated not only by the downregulation of Survivin but also through induced expression of the proapoptotic protein Bim, repression of the anti-apoptotic protein Mcl-1, followed by activation of caspases.

Citation Format: Eswar Shankar, Sarah L. Corum, Scott M. Welford, David Danielpour. Survivin Suppression by YM155 involves downregulation of Cyclin Ds and Activation of Rb. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5175. doi:10.1158/1538-7445.AM2013-5175