Abstract 4447: Targeting Hsp90 with small molecule inhibitors induces the overexpression of the anti-apoptotic molecule, survivin, in human cancer cells

Abstract

Abstract Survivin is a dual functioning protein. It inhibits the apoptosis of cells by inhibiting caspases, and also promotes cell growth by stabilizing microtubules during mitosis. Furthermore, over-expression of survivin has been shown to induce drug resistance to various chemotherapeutic compounds. Since the molecular chaperone Hsp90 binds and stabilizes survivin, it is widely believed that down-regulation of survivin is one of the important therapeutic functions of Hsp90 inhibitors such as the phase III clinically trialed compound 17-AAG. However, Hsp90 interferes with a number of molecules that positively regulate the intracellular level of survivin, raising the question that clinical use of Hsp90 inhibitors may indirectly induce survivin expression and subsequently promote cancer progression under certain circumstances. Here, we demonstrated that Hsp90 inhibitors, geldanamycin and 17-AAG, induced the over-expression of survivin in three different human cancer cell lines as shown by western blotting. Increased survivin mRNA transcripts were observed in 17-AAG and geldanamycin-treated HT-29 and HONE-1 cancer cells. Interestingly, real-time PCR and translation inhibition studies revealed that survivin was over-expressed partially through the up-regulation of protein translation instead of gene transcription in A549 cancer cells. In addition, 17-AAG-treated A549, HONE-1 and HT-29 cells showed reduced amount of 26S proteasome and decreased proteasomal activity while inhibition of 26S proteasome further increased the amount of survivin protein in cells. At the functional level, down-regulation of survivin by siRNA further increased the drug sensitivity to 17-AAG in the tested cancer cell lines. In conclusion, we showed for the first time that targeting Hsp90 induced the over-expression of survivin through various mechanisms in cancer cells. These data indicate that down-regulation of survivin is not a definite therapeutic function of Hsp90 inhibitors. The current study suggests that dual inhibition of Hsp90 and survivin may be warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4447.