title: Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia.
abstract: To identify FDA-approved agents targeting leukemic cells, we performed a chemical screen on two human leukemic cell lines and identified the antimicrobial tigecycline. A genome-wide screen in yeast identified mitochondrial translation inhibition as the mechanism of tigecycline-mediated lethality. Tigecycline selectively killed leukemia stem and progenitor cells compared to their normal counterparts and also showed antileukemic activity in mouse models of human leukemia. ShRNA-mediated knockdown of EF-Tu mitochondrial translation factor in leukemic cells reproduced the antileukemia activity of tigecycline. These effects were derivative of mitochondrial biogenesis that, together with an increased basal oxygen consumption, proved to be enhanced in AML versus normal hematopoietic cells and were also important for their difference in tigecycline sensitivity.
authors.affiliation: Campbell Family Cancer Research Institute, Princess Margaret Hospital, Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Marko
authors.initials: M
authors.lastname: Skrtić
authors.forename: Shrivani
authors.initials: S
authors.lastname: Sriskanthadevan
authors.forename: Bozhena
authors.initials: B
authors.lastname: Jhas
authors.forename: Marinella
authors.initials: M
authors.lastname: Gebbia
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.forename: Zezhou
authors.initials: Z
authors.lastname: Wang
authors.forename: Rose
authors.initials: R
authors.lastname: Hurren
authors.forename: Yulia
authors.initials: Y
authors.lastname: Jitkova
authors.forename: Marcela
authors.initials: M
authors.lastname: Gronda
authors.forename: Neil
authors.initials: N
authors.lastname: Maclean
authors.forename: Courteney K
authors.initials: CK
authors.lastname: Lai
authors.forename: Yanina
authors.initials: Y
authors.lastname: Eberhard
authors.forename: Justyna
authors.initials: J
authors.lastname: Bartoszko
authors.forename: Paul
authors.initials: P
authors.lastname: Spagnuolo
authors.forename: Angela C
authors.initials: AC
authors.lastname: Rutledge
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.forename: Troy
authors.initials: T
authors.lastname: Ketela
authors.forename: Jason
authors.initials: J
authors.lastname: Moffat
authors.forename: Brian H
authors.initials: BH
authors.lastname: Robinson
authors.forename: Jessie H
authors.initials: JH
authors.lastname: Cameron
authors.forename: Jeffery
authors.initials: J
authors.lastname: Wrana
authors.forename: Connie J
authors.initials: CJ
authors.lastname: Eaves
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: Jean C Y
authors.initials: JC
authors.lastname: Wang
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.forename: Keith
authors.initials: K
authors.lastname: Humphries
authors.forename: Corey
authors.initials: C
authors.lastname: Nislow
authors.forename: Guri
authors.initials: G
authors.lastname: Giaever
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D050259:Genes, Mitochondrial; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D008911:Minocycline / Q000031:analogs & derivatives* / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D010444:Peptide Elongation Factor Tu / Q000235:genetics; D014176:Protein Biosynthesis / Q000187:drug effects*; D034741:RNA, Small Interfering; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D000078304:Tigecycline
chemical_list: D000970:Antineoplastic Agents; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D000078304:Tigecycline; D010444:Peptide Elongation Factor Tu; D008911:Minocycline
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