Abstract 1804: New insights in the induction of cell death by the imidazolium based compound YM155

Abstract

Abstract The inhibitor of apoptosis protein (IAP) Survivin is robustly over-expressed in a variety of cancers including prostate carcinomas, and has been shown to play pivotal roles in cancer progression and resistance to chemotherapy. The imidazolium based small molecule YM155, which was first identified as a robust suppressor of the Survivin promoter of PC-3 prostate carcinoma and under clinical investigation for the treatment of multiple cancers, is a potent apoptosis inducer of castration-resistant prostate cancer (CRPC) cells. However, the mechanisms by which it inhibits the expression of Survivin and kills cancer cells remain unclear. Here we studied early signaling responses to YM155 in a panel of prostate and kidney cancer cell lines in standard cell culture conditions and showed that YM155 rapidly decreases the expression of cyclin Ds 1, 2 and 3, and activates the retinoblastoma protein (Rb), leading to the downregulation of the Survivin promoter. However, despite the robust lost of cyclin Ds, YM155 promotes an S-phase arrest rather than arrests cells at either G1 or G2/M. This suggests cell killing by YM155 involves S-phase arrest, consistent with a DNA damage response. In addition, we show that YM155 also downregulates the expression of the anti-apoptotic protein Mcl-1 and induces the expression of proapoptotic proteins Bad and Bim followed by the activation of caspases -3 and -8. Moreover, early time course experiments show that YM155 induces rapid (10 - 60 min) but transient activation of Akt and Erk1/2 followed by a marked suppression by 4 to 8 h likely via the induced expression of phosphatases 1 and 5 (DUSP1 and 5). Taken together we suggest YM155 induces apoptosis of prostate epithelial cells through a complex mechanism involving Akt, Erk1/2, DUSPs, cyclin Ds, Rb, S-phase arrest, Bim, Bad, Mcl-1,Survivin, and activation of caspases -3 and -8. Citation Format: David Danielpour, Eswar Shankar, Sarah L. Corum. New insights in the induction of cell death by the imidazolium based compound YM155. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1804. doi:10.1158/1538-7445.AM2014-1804