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Cancer Cell. 2019 May 13;35(5):721-737.e9. doi: 10.1016/j.ccell.2019.03.014. Epub 2019 May 2.

Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality.

Author information

1
The University of Texas MD Anderson Cancer Center, Molecular Hematology and Therapy, Department of Leukemia, Houston, TX 77030, USA.
2
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L7, Canada.
3
The University of Texas MD Anderson Cancer Center; Department of Lymphoma and Myeloma, Houston, TX 77030, USA.
4
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
5
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
6
The University of Texas MD Anderson Cancer Center, Bioinformatics and Comp Biology, Houston, TX 77030, USA.
7
The University of Texas MD Anderson Cancer Center, Genomic Medicine, Houston, TX 77030, USA.
8
Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
9
The University of Texas MD Anderson Cancer Center, Molecular Hematology and Therapy, Department of Leukemia, Houston, TX 77030, USA; Saga University, Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga 849-8501, Japan.
10
Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
11
The University of Texas MD Anderson Cancer Center; Department of Leukemia, Houston, TX 77030, USA.
12
Oncoceutics, Inc., Philadelphia, PA 19104, USA.
13
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
14
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: aaron.schimmer@uhn.ca.
15
The University of Texas MD Anderson Cancer Center, Molecular Hematology and Therapy, Department of Leukemia, Houston, TX 77030, USA; The University of Texas MD Anderson Cancer Center; Department of Leukemia, Houston, TX 77030, USA. Electronic address: mandreef@mdanderson.org.

Abstract

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.

KEYWORDS:

acute myeloid leukemia; cancer; imipridone; lymphoma; mitochondrial ClpP; mitochondrial proteolysis; oxidative phosphorylation; respiratory chain complex

PMID:
31056398
PMCID:
PMC6620028
[Available on 2020-05-13]
DOI:
10.1016/j.ccell.2019.03.014

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