Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality.
The mitochondrial caseinolytic protease P (ClpP) plays a central role in mitochondrial protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the protease selectively kills cancer cells, independently of p53 status, by selective degradation of its respiratory chain protein substrates and disrupts mitochondrial structure and ... function, while it does not affect non-malignant cells. We identified imipridones as potent activators of ClpP. Through biochemical studies and crystallography, we show that imipridones bind ClpP non-covalently and induce proteolysis by diverse structural changes. Imipridones are presently in clinical trials. Our findings suggest a general concept of inducing cancer cell lethality through activation of mitochondrial proteolysis.
Mesh Terms:
Animals, Cell Line, Tumor, Cell Survival, Crystallography, X-Ray, Drug Screening Assays, Antitumor, Endopeptidase Clp, Female, HCT116 Cells, HEK293 Cells, Heterocyclic Compounds, 4 or More Rings, Humans, Leukemia, Myeloid, Acute, Mice, Mitochondria, Models, Molecular, Point Mutation, Protein Conformation, Proteolysis, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Animals, Cell Line, Tumor, Cell Survival, Crystallography, X-Ray, Drug Screening Assays, Antitumor, Endopeptidase Clp, Female, HCT116 Cells, HEK293 Cells, Heterocyclic Compounds, 4 or More Rings, Humans, Leukemia, Myeloid, Acute, Mice, Mitochondria, Models, Molecular, Point Mutation, Protein Conformation, Proteolysis, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Cancer Cell
Date: Dec. 13, 2018
PubMed ID: 31056398
View in: Pubmed Google Scholar
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