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http://dx.doi.org/10.5352/JLS.2016.26.7.826

SIRT1 Inhibitor Enhances Hsp90 Inhibitor-mediated Abrogation of Hsp90 Chaperone Function and Potentiates the Cytotoxicity of Hsp90 Inhibitor in Chemo-resistant Human Cancer Cells  

Moon, Hyun-Jung (Department of Biochemistry and Pusan National University School of Medicine)
Lee, Su-Hoon (Department of Biochemistry and Pusan National University School of Medicine)
Kim, Hak-Bong (Department of Biochemistry and Pusan National University School of Medicine)
Lee, Kyoung-A (Department of Biochemistry and Pusan National University School of Medicine)
Kang, Chi-Dug (Department of Biochemistry and Pusan National University School of Medicine)
Kim, Sun-Hee (Department of Biochemistry and Pusan National University School of Medicine)
Publication Information
Journal of Life Science / v.26, no.7, 2016 , pp. 826-834 More about this Journal
Abstract
The present investigation was undertaken to examine the effectiveness of the combination treatment of an Hsp90 inhibitor and a SIRT1 inhibitor on suppressing the growth of chemo-resistant human cancer cells. We showed that inhibition of SIRT1 effectively potentiated the cytotoxicity of 17-allylamino-17-demethoxygeldanamycin (17-AAG) and reversed Hsp90 inhibitor resistance in multidrug-resistant (MDR) human ovarian HeyA8-MDR cells. Amurensin G, a potent natural SIRT1 inhibitor, enhanced Hsp90 inhibitor-mediated abrogation of the Hsp90 chaperone function and accelerated degradation of mutated p53 (mut p53), an Hsp90 client protein, by up-regulation of ubiquitin ligase CHIP. Knock-down of CHIP significantly attenuated amurensin G-induced mut p53 degradation. Down-regulation of mut p53 reduced the expression of heat shock factor1 (HSF1)/heat shock proteins (Hsps), a major cause of Hsp90 inhibitor resistance, which led to sensitization of the MDR cells to the Hsp90 inhibitor by the SIRT1 inhibitor. Amurensin G potentiated cytotoxicity of the Hsp90 inhibitor in HeyA8-MDR cells through suppression of 17-AAG-induced Hsp70 and Hsp27 induction via down-regulation of mut p53/HSF1, and it caused activation of PARP and inhibition of Bcl-2. Our data suggests that SIRT1 inhibitors could be used to sensitize MDR cells to Hsp90 inhibitors, possibly through suppression of the mut p53/HSF1-dependent pathway, and a novel mut p53-directed action of SIRT1 inhibition could effectively prevent mut p53 accumulation in MDR cells.
Keywords
Cancer; HSF1; Hsp70; Hsp90 inhibitor; SIRT1 inhibitor;
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