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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinase Kinases
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Biocatalysis / drug effects
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Cell Cycle Proteins
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Cell Death / drug effects
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Cell Proliferation / drug effects
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Enzyme Activation / drug effects
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Humans
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Leukemia, Myeloid, Acute / enzymology*
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / pathology
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Metformin / pharmacology
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Mice
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Neoplasm Proteins / biosynthesis*
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Polyribosomes / drug effects
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Polyribosomes / metabolism
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Protein Biosynthesis* / drug effects
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases / metabolism*
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Signal Transduction* / drug effects
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TOR Serine-Threonine Kinases / metabolism*
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Neoplasm Proteins
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Phosphoproteins
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Metformin
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Protein Kinases
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Protein Serine-Threonine Kinases
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STK11 protein, human
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TOR Serine-Threonine Kinases
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AMP-Activated Protein Kinase Kinases