1. Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress.
- Author
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Wang CY, Guo ST, Wang JY, Liu F, Zhang YY, Yari H, Yan XG, Jin L, Zhang XD, and Jiang CC
- Subjects
- Animals, Apoptosis drug effects, Apoptosis genetics, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins metabolism, Bcl-2-Like Protein 11 genetics, 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, Gene Expression, Heat-Shock Proteins antagonists & inhibitors, Humans, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mitochondrial Proteins, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Tumor Burden drug effects, Tumor Burden genetics, X-Box Binding Protein 1 antagonists & inhibitors, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Bcl-2-Like Protein 11 metabolism, Endoplasmic Reticulum Stress drug effects, HSP90 Heat-Shock Proteins antagonists & inhibitors, Isoxazoles pharmacology, Mutation, Proto-Oncogene Proteins p21(ras) genetics, Resorcinols pharmacology
- 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., (©2016 American Association for Cancer Research.)
- Published
- 2016
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