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Mol Cancer Ther. 2017 Sep;16(9):1979-1988. doi: 10.1158/1535-7163.MCT-17-0032. Epub 2017 Jun 15.

FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors.

Author information

1
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
2
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
3
College of Life Sciences, Sichuan University, Chengdu, Sichuan, PR China.
4
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
5
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
6
College of Life Sciences, Sichuan University, Chengdu, Sichuan, PR China. zhanglx@upmc.edu fundzou@scu.edu.cn.
7
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. zhanglx@upmc.edu fundzou@scu.edu.cn.

Abstract

Heat shock protein 90 (Hsp90) is widely overexpressed in cancer cells and necessary for maintenance of malignant phenotypes. Hsp90 inhibition induces tumor cell death through degradation of its client oncoproteins and has shown promises in preclinical studies. However, the mechanism by which Hsp90 inhibitors kill tumor cells is not well-understood. Biomarkers associated with differential sensitivity and resistance to Hsp90 inhibitors remain to be identified. In this study, we found that colorectal cancer cells containing inactivating mutations of FBW7, a tumor suppressor and E3 ubiquitin ligase, are intrinsically insensitive to Hsp90 inhibitors. The insensitive colorectal cancer cells lack degradation of Mcl-1, a prosurvival Bcl-2 family protein. Hsp90 inhibition promotes GSK3β-dependent phosphorylation of Mcl-1, which subsequently binds to FBW7 and undergoes ubiquitination and proteasomal degradation. Specifically blocking Mcl-1 phosphorylation by genetic knock-in abrogates its degradation and renders in vitro and in vivo resistance to Hsp90 inhibitors, which can be overcame by Mcl-1-selective small-molecule inhibitors. Collectively, our findings demonstrate a key role of GSK3β/FBW7-dependent Mcl-1 degradation in killing of colorectal cancer cells by Hsp90 inhibitors and suggest FBW7 mutational status as a biomarker for Hsp90-targeted therapy. Mol Cancer Ther; 16(9); 1979-88. ©2017 AACR.

PMID:
28619760
PMCID:
PMC5587378
DOI:
10.1158/1535-7163.MCT-17-0032
[Indexed for MEDLINE]
Free PMC Article

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