title: The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation.
abstract: Finding an effective treatment for acute myeloid leukemia (AML) remains a challenge, and all cellular processes that are deregulated in AML cells should be considered in the design of targeted therapies. We show in our current study that the LKB1/AMPK/TSC tumor suppressor axis is functional in AML and can be activated by the biguanide molecule metformin, resulting in a specific inhibition of mammalian target of rapamycin (mTOR) catalytic activity. This induces a multisite dephosphorylation of the key translation regulator, 4E-BP1, which markedly inhibits the initiation step of mRNA translation. Consequently, metformin reduces the recruitment of mRNA molecules encoding oncogenic proteins to the polysomes, resulting in a strong antileukemic activity against primary AML cells while sparing normal hematopoiesis ex vivo and significantly reducing the growth of AML cells in nude mice. The induction of the LKB1/AMPK tumor-suppressor pathway thus represents a promising new strategy for AML therapy.
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France.
authors.forename: Alexa S
authors.initials: AS
authors.lastname: Green
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chapuis
authors.forename: Thiago Trovati
authors.initials: TT
authors.lastname: Maciel
authors.forename: Lise
authors.initials: L
authors.lastname: Willems
authors.forename: Mireille
authors.initials: M
authors.lastname: Lambert
authors.forename: Christophe
authors.initials: C
authors.lastname: Arnoult
authors.forename: Olivier
authors.initials: O
authors.lastname: Boyer
authors.forename: Valerie
authors.initials: V
authors.lastname: Bardet
authors.forename: Sophie
authors.initials: S
authors.lastname: Park
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.forename: François
authors.initials: F
authors.lastname: Dreyfus
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.forename: Ivan Cruz
authors.initials: IC
authors.lastname: Moura
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacombe
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.forename: Didier
authors.initials: D
authors.lastname: Bouscary
authors.forename: Jerome
authors.initials: J
authors.lastname: Tamburini
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011132:Polyribosomes / Q000187:drug effects / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D008687:Metformin; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases