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

Hak-Bong Kim; Su-Hoon Lee; Jee-Hyun Um; Won Keun Oh; Dong-Wan Kim; Chi-Dug Kang; Sun-Hee Kim

doi:10.18632/oncotarget.5343

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

Oncotarget. 2015 Nov 3;6(34):36202-18. doi: 10.18632/oncotarget.5343.

Authors

Hak-Bong Kim¹, Su-Hoon Lee¹, Jee-Hyun Um², Won Keun Oh³, Dong-Wan Kim⁴, Chi-Dug Kang¹, Sun-Hee Kim¹

Affiliations

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.

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.

Keywords: Hsp70; Hsp90 inhibitor; MDR; P-gp; SIRT1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Benzoquinones / pharmacology
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Carbazoles / pharmacology
Cell Line, Tumor
Dibenzocycloheptenes / pharmacology
Down-Regulation
Drug Resistance, Neoplasm
Drug Synergism
Gene Knockdown Techniques
HSP70 Heat-Shock Proteins / metabolism
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / metabolism
Humans
Isoxazoles / pharmacology
Lactams, Macrocyclic / pharmacology
MCF-7 Cells
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
Resorcinols / pharmacology
Sirtuin 1 / antagonists & inhibitors*
Sirtuin 1 / genetics
Sirtuin 1 / metabolism

Substances

5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide
Benzoquinones
Carbazoles
Dibenzocycloheptenes
HSP70 Heat-Shock Proteins
HSP90 Heat-Shock Proteins
Isoxazoles
Lactams, Macrocyclic
Resorcinols
amurensin G
tanespimycin
SIRT1 protein, human
Sirtuin 1