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Cancer Cell. 2015 Jun 8;27(6):864-76. doi: 10.1016/j.ccell.2015.05.004.

Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia.

Author information

1
Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
2
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
3
Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
4
Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
5
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Molecular Genetics, Donnelly Centre for Cellular and Biomolecular Research, Toronto, ON M5S 3E1, Canada.
8
Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
9
Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
10
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA.
11
Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada.
12
Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada. Electronic address: aaron.schimmer@utoronto.ca.

Abstract

From an shRNA screen, we identified ClpP as a member of the mitochondrial proteome whose knockdown reduced the viability of K562 leukemic cells. Expression of this mitochondrial protease that has structural similarity to the cytoplasmic proteosome is increased in leukemic cells from approximately half of all patients with AML. Genetic or chemical inhibition of ClpP killed cells from both human AML cell lines and primary samples in which the cells showed elevated ClpP expression but did not affect their normal counterparts. Importantly, Clpp knockout mice were viable with normal hematopoiesis. Mechanistically, we found that ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes, and knockdown of ClpP in leukemic cells inhibited oxidative phosphorylation and mitochondrial metabolism.

PMID:
26058080
PMCID:
PMC4461837
DOI:
10.1016/j.ccell.2015.05.004
[Indexed for MEDLINE]
Free PMC Article

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