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Cancer Res. 2017 May 1;77(9):2512-2521. doi: 10.1158/0008-5472.CAN-16-3242. Epub 2017 Feb 15.

Mcl-1 Degradation Is Required for Targeted Therapeutics to Eradicate Colon Cancer Cells.

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, P.R. 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
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. zhanglx@upmc.edu.

Abstract

The Bcl-2 family protein Mcl-1 is often degraded in cancer cells subjected to effective therapeutic treatment, and defective Mcl-1 degradation has been associated with intrinsic and acquired drug resistance. However, a causal relationship between Mcl-1 degradation and anticancer drug responses has not been directly established, especially in solid tumor cells where Mcl-1 inhibition alone is insufficient to trigger cell death. In this study, we present evidence that Mcl-1 participates directly in determining effective therapeutic responses in colon cancer cells. In this setting, Mcl-1 degradation was induced by a variety of multikinase inhibitor drugs, where it relied upon GSK3β phosphorylation and FBW7-dependent ubiquitination. Specific blockade by genetic knock-in (KI) abolished apoptotic responses and conferred resistance to kinase inhibitors. Mcl-1-KI also suppressed the antiangiogenic and anti-hypoxic effects of kinase inhibitors in the tumor microenvironment. Interestingly, these same inhibitors also induced the BH3-only Bcl-2 family protein PUMA, which is required for apoptosis. Degradation-resistant Mcl-1 bound and sequestered PUMA from other prosurvival proteins to maintain cell survival, which was abolished by small-molecule Mcl-1 inhibitors. Our findings establish a pivotal role for Mcl-1 degradation in the response of colon cancer cells to targeted therapeutics, and they provide a useful rational platform to develop Mcl-1-targeting agents that can overcome drug resistance. Cancer Res; 77(9); 2512-21. ©2017 AACR.

PMID:
28202514
PMCID:
PMC5626525
DOI:
10.1158/0008-5472.CAN-16-3242
[Indexed for MEDLINE]
Free PMC Article

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