Abstract
BackgroundSurvivin is a dual functioning protein. It inhibits the apoptosis of cancer cells by inhibiting caspases, and also promotes cancer cell growth by stabilizing microtubules during mitosis. 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 up-regulate the intracellular level of survivin, raising the question that clinical use of Hsp90 inhibitors may indirectly induce survivin expression and subsequently enhance cancer anti-drug responses. The purpose of this study is to determine whether targeting Hsp90 can alter survivin expression differently in different cancer cell lines and to explore possible mechanisms that cause the alteration in survivin expression.ResultsHere, 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 proteasomal activity while inhibition of 26S proteasome activity 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.ConclusionsWe showed for the first time that down-regulation of survivin is not a definite therapeutic function of Hsp90 inhibitors. Instead, targeting Hsp90 with small molecule inhibitors will induce the over-expression of survivin in certain cancer cell lines and subsequently enhances the ability of cell survival in drug-treated situations. The current study suggests that dual inhibition of Hsp90 and survivin may be warranted.
Highlights
Heat shock protein 90 (Hsp90) is a molecular chaperone that assists the correct folding and stabilization of various proteins in cells
Targeting Hsp90 induces the over-expression of survivin in cancer cells To determine whether the inhibition of Hsp90 with small molecule inhibitors was able to affect survivin expression, we treated human cancer cells with Hsp90 inhibitors geldanamycin and 17-AAG. 17-AAG is a selective Hsp90 inhibitor that exhibited therapeutic activities in various cancers and is currently undergoing phase III clinical trials [17,21,22,23,24]
In A549 cells, targeting Hsp90 with 17-AAG and geldanamycin slightly induced the baseline expression of Hsp90 as previously reported (Figure 1B) [5]
Summary
Heat shock protein 90 (Hsp90) is a molecular chaperone that assists the correct folding and stabilization of various proteins in cells. Unlike other IAPs, survivin is a bifunctional protein that functions as a key regulator of mitosis and inhibitor of programmed cell death. It is well-demonstrated that the over-expression of survivin induces resistance to various anti-cancer therapies such as chemotherapy and radiation therapy in cancer cells [812]. It inhibits the apoptosis of cancer cells by inhibiting caspases, and promotes cancer cell growth by stabilizing microtubules during mitosis. Hsp interferes with a number of molecules that up-regulate the intracellular level of survivin, raising the question that clinical use of Hsp inhibitors may indirectly induce survivin expression and subsequently enhance cancer anti-drug responses. The purpose of this study is to determine whether targeting Hsp can alter survivin expression differently in different cancer cell lines and to explore possible mechanisms that cause the alteration in survivin expression
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