Abstract
The effectiveness of Hsp90 inhibitors as anticancer agents was limited in multidrug-resistant (MDR) human cancer cells due to induction of heat shock proteins (Hsps) such as Hsp70/Hsp27 and P-glycoprotein (P-gp)-mediated efflux. In the present study, we showed that resistance to Hsp90 inhibitors of MDR human cancer cells could be overcome with SIRT1 inhibition. SIRT1 knock-down or SIRT1 inhibitors (amurensin G and EX527) effectively suppressed the resistance to Hsp90 inhibitors (17-AAG and AUY922) in several MDR variants of human lymphoblastic leukemia and human breast cancer cell lines. SIRT1 inhibition down-regulated the expression of heat shock factor 1 (HSF1) and subsequently Hsps and facilitated Hsp90 multichaperone complex disruption via hyperacetylation of Hsp90/Hsp70. These findings were followed by acceleration of ubiquitin ligase CHIP-mediated mutant p53 (mut p53) degradation and subsequent down-regulation of P-gp in 17-AAG-treated MDR cancer cells expressing P-gp and mut p53 after inhibition of SIRT1. Therefore, combined treatment with Hsp90 inhibitor and SIRT1 inhibitor could be a more effective therapeutic approach for Hsp90 inhibitor-resistant MDR cells via down-regulation of HSF1/Hsps, mut p53 and P-gp.
Highlights
Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for the stability and function of numerous oncoproteins that promote the growth and/or survival of cancer cells, and may serve as a therapeutic target for the treatment of cancer [1]
To compare the susceptibility of Hsp90 inhibitormediated cytotoxicity between CCRF-CEM human leukemia cells, MCF-7 human breast cancer cells and HeyA8 human ovarian cancer cells, and their respective MDR variants, they were treated with increasing doses of Hsp90 inhibitors including 17-AAG
These results suggest that P-gp expression might contribute to resistance of MDR cells to Hsp90 inhibitors
Summary
Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for the stability and function of numerous oncoproteins that promote the growth and/or survival of cancer cells, and may serve as a therapeutic target for the treatment of cancer [1]. It has been demonstrated that in the absence of Hsp activity, the less stable unfolded mut p53 protein preferentially associate in a complex with Hsp and CHIP (carboxyl terminus of Hsp70-interacting protein) ubiquitin ligase [17], which has a major role for in the degradation of unfolded mut p53, with little or no roles for CHIP in degrading wild-type p53 protein [20]. This CHIP-mediated degradation of mut p53 would suppress the expression of MDR1/P-gp in MDR cells
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