Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress

Chun Yan Wang; Su Tang Guo; Jia Yu Wang; Fen Liu; Yuan Yuan Zhang; Hamed Yari; Xu Guang Yan; Lei Jin; Xu Dong Zhang; Chen Chen Jiang

doi:10.1158/1535-7163.MCT-15-0778

Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress

Mol Cancer Ther. 2016 Mar;15(3):448-59. doi: 10.1158/1535-7163.MCT-15-0778. Epub 2016 Feb 1.

Authors

Affiliations

¹ School of Biomedical Sciences and Pharmacy, The University of Newcastle, New South Wales, Australia. Department of Molecular Biology, Shanxi Cancer Hospital and Institute, The Affiliated Cancer Hospital of Shanxi Medical University, Shanxi, China.
² School of Biomedical Sciences and Pharmacy, The University of Newcastle, New South Wales, Australia.
³ School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia.
⁴ School of Biomedical Sciences and Pharmacy, The University of Newcastle, New South Wales, Australia. Xu.Zhang@newcastle.edu.au Chenchen.Jiang@newcastle.edu.au.
⁵ School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia. Xu.Zhang@newcastle.edu.au Chenchen.Jiang@newcastle.edu.au.

PMID: 26832792
DOI: 10.1158/1535-7163.MCT-15-0778

Abstract

Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. Remarkably, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and the agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Apoptosis / genetics
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism
Bcl-2-Like Protein 11 / genetics
Bcl-2-Like Protein 11 / metabolism*
Cell Line, Tumor
Cell Survival / drug effects
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology
Disease Models, Animal
Drug Resistance, Neoplasm / genetics
Endoplasmic Reticulum Chaperone BiP
Endoplasmic Reticulum Stress / drug effects*
Gene Expression
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
Heat-Shock Proteins / antagonists & inhibitors
Humans
Isoxazoles / pharmacology*
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mitochondrial Proteins
Mutation*
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins p21(ras) / genetics*
Resorcinols / pharmacology*
Tumor Burden / drug effects
Tumor Burden / genetics
X-Box Binding Protein 1 / antagonists & inhibitors
Xenograft Model Antitumor Assays

Substances

5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
Antineoplastic Agents
Apoptosis Regulatory Proteins
BBC3 protein, human
BIK protein, human
Bcl-2-Like Protein 11
Endoplasmic Reticulum Chaperone BiP
HSP90 Heat-Shock Proteins
HSPA5 protein, human
Heat-Shock Proteins
Isoxazoles
Membrane Proteins
Mitochondrial Proteins
Proto-Oncogene Proteins
Resorcinols
X-Box Binding Protein 1
Proto-Oncogene Proteins p21(ras)