Sensitization of multidrug-resistant human cancer cells to Hsp90 inhibitors by down-regulation of SIRT1
- Authors
- Kim, Hak-Bong; Lee, Su-Hoon; Um, Jee-Hyun; Oh, Won Keun; Kim, Dong-Wan; Kang, Chi-Dug; Kim, Sun-Hee
- Issue Date
- 3-Nov-2015
- Publisher
- IMPACT JOURNALS LLC
- Keywords
- Hsp90 inhibitor; MDR; SIRT1; P-gp; Hsp70
- Citation
- ONCOTARGET, v.6, no.34, pp.36202 - 36218
- Journal Title
- ONCOTARGET
- Volume
- 6
- Number
- 34
- Start Page
- 36202
- End Page
- 36218
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/9916
- DOI
- 10.18632/oncotarget.5343
- ISSN
- 1949-2553
- 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-AAGtreated 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 downregulation of HSF1/Hsps, mut p53 and P-gp.
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