title: Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia.
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.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Alicia
authors.initials: A
authors.lastname: Cole
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Zezhou
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Etienne
authors.initials: E
authors.lastname: Coyaud
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Veronique
authors.initials: V
authors.lastname: Voisin
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Marcela
authors.initials: M
authors.lastname: Gronda
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Jitkova
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Rachel
authors.initials: R
authors.lastname: Mattson
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Rose
authors.initials: R
authors.lastname: Hurren
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Sonja
authors.initials: S
authors.lastname: Babovic
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Neil
authors.initials: N
authors.lastname: Maclean
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Restall
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Danny V
authors.initials: DV
authors.lastname: Jeyaraju
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Mahadeo A
authors.initials: MA
authors.lastname: Sukhai
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Swayam
authors.initials: S
authors.lastname: Prabha
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Shaheena
authors.initials: S
authors.lastname: Bashir
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Ramakrishnan
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Elisa
authors.initials: E
authors.lastname: Leung
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yi Hua
authors.initials: YH
authors.lastname: Qia
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Nianxian
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Combes
authors.affiliation: Department of Molecular Genetics, Donnelly Centre for Cellular and Biomolecular Research, Toronto, ON M5S 3E1, Canada.
authors.forename: Troy
authors.initials: T
authors.lastname: Ketela
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Fengshu
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Walid A
authors.initials: WA
authors.lastname: Houry
authors.affiliation: Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Aman
authors.affiliation: 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.
authors.forename: Rima
authors.initials: R
authors.lastname: Al-Awar
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Erno
authors.initials: E
authors.lastname: Wienholds
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Chang Jiang
authors.initials: CJ
authors.lastname: Xu
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Dick
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Jean C Y
authors.initials: JC
authors.lastname: Wang
authors.affiliation: Department of Molecular Genetics, Donnelly Centre for Cellular and Biomolecular Research, Toronto, ON M5S 3E1, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Moffat
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada; Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC V5Z 1L3, Canada.
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Zhenyue
authors.initials: Z
authors.lastname: Hao
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Raught
authors.affiliation: 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.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
mesh_terms: D000818:Animals; D049071:Endopeptidase Clp / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; C568646:ClpP protein, human; D049071:Endopeptidase Clp