Sensitization of multidrug-resistant human cancer cells to Hsp90 inhibitors by down-regulation of SIRT1

// Hak-Bong Kim 1 , Su-Hoon Lee 1 , Jee-Hyun Um 2 , Won Keun Oh 3 , Dong-Wan Kim 4 , Chi-Dug Kang 1 , Sun-Hee Kim 1 1 Department of Biochemistry, Pusan National University School of Medicine, Yangsan 626-870, Korea 2 Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 406-840, Korea 3 Korea Bioactive Natural Material Bank, College of Pharmacy, Seoul National University, Seoul 151-818, Korea 4 Department of Microbiology, College of Natural Sciences, Chang Won National University, Chang Won 641-773, Korea Correspondence to: Chi-Dug Kang, e-mail: kcdshbw@pusan.ac.kr Sun-Hee kim, e-mail: ksh7738@pusan.ac.kr Keywords: Hsp90 inhibitor, MDR, SIRT1, P-gp, Hsp70 Received: June 10, 2015 Accepted: August 26, 2015 Published: September 25, 2015 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.