title: Mcl-1 Degradation Is Required for Targeted Therapeutics to Eradicate Colon Cancer Cells.
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.
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Jingshan
authors.initials: J
authors.lastname: Tong
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.|College of Life Sciences, Sichuan University, Chengdu, Sichuan, P.R. China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Tan
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Dongshi
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Nikolovska-Coleska
authors.affiliation: College of Life Sciences, Sichuan University, Chengdu, Sichuan, P.R. China.
authors.forename: Fangdong
authors.initials: F
authors.lastname: Zou
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.|Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. zhanglx@upmc.edu.|Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D055879:Gene Knock-In Techniques; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D059748:Proteolysis / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D044767:Ubiquitin-Protein Ligases; D000071679:Glycogen Synthase Kinase 3 beta