Abstract
Global cleavage of cellular proteins by activated caspases is a hallmark of apoptosis, which causes biochemical collapse of the cell. Recent studies suggest that, rather than completely destroying a protein, caspase cleavage can confer novel characteristics or functions. In this respect, the post-caspase role of Bcl-2 family proteins remains uncharacterized. Here, we showed that Mcl-1, a pro-survival member of the Bcl-2 family, was cleaved by caspase-3 in non-small cell lung cancer (NSCLC) cells undergoing chemotherapeutic agent-triggered apoptosis. Caspase cleavage partially impaired the anti-apoptotic activity of Mcl-1 by reducing its mitochondrial localization and impeding its association with the permeability transition pore-forming protein Bak. However, the stability of cleaved Mcl-1 was markedly enhanced because it was more refractory to ubiquitination-dependent proteasomal degradation, thereby improving cell viability to a greater extent than full-length Mcl-1 when transiently expressed in NSCLC cells. These findings shed new light on the role of Mcl-1 in apoptosis and suggest potential novel targets for optimizing the tumoricidal capacity of chemotherapy.
Keywords:
Bak; Chemotherapy; Lung cancer; Mcl-1; Proteasomal degradation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Binding Sites
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism*
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Carcinoma, Non-Small-Cell Lung / pathology
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Caspase 3 / chemistry*
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cisplatin / pharmacology
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Docetaxel / pharmacology
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Gene Expression
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology
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Mitochondria / drug effects
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Mitochondria / metabolism
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Molecular Docking Simulation
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Myeloid Cell Leukemia Sequence 1 Protein / chemistry*
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Proteasome Endopeptidase Complex / metabolism*
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Conformation, beta-Strand
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Protein Interaction Domains and Motifs
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Proteolysis
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bcl-2 Homologous Antagonist-Killer Protein / chemistry*
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bcl-2 Homologous Antagonist-Killer Protein / genetics
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
Substances
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Antineoplastic Agents
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BAK1 protein, human
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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bcl-2 Homologous Antagonist-Killer Protein
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Docetaxel
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CASP3 protein, human
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Caspase 3
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Proteasome Endopeptidase Complex
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Cisplatin