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Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality

2019; Cell Press; Volume: 35; Issue: 5 Linguagem: Inglês

10.1016/j.ccell.2019.03.014

1878-3686

Jo Ishizawa, Sarah F. Zarabi, R. Eric Davis, Ondrej Halgas, Takenobu Nii, Yulia Jitkova, Ran Zhao, Jonathan St‐Germain, Lauren Heese, Grace Egan, Vivian Ruvolo, Samir H. Barghout, Yuki Nishida, Rose Hurren, Wencai Ma, Marcela Gronda, Todd Link, Keith S. Wong, Mark Mabanglo, Kensuke Kojima, Gautam Borthakur, Neil MacLean, Man Chun John, Andrew B. Leber, Mark D. Minden, Walid A. Houry, Hagop M. Kantarjian, Martin Stogniew, Brian Raught, E.F. Pai, Aaron D. Schimmer, Michael Andreeff,

RNA modifications and cancer

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.