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The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation

Published inBlood, vol. 116, no. 20, p. 4262-4273
Publication date2010-11-18
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.

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Keywords
  • Ampk
  • Leukemia
  • Myelocytic
  • Acute
  • Metformin
  • Mtor serine-threonine kinases
  • Stk11 gene
  • Translation
  • Genetic
  • Tumor suppressor genes
  • Polyribosomes
  • Molecule
  • Phosphorylation
Affiliation Not a UNIGE publication
Citation (ISO format)
GREEN, Alexa S. et al. The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation. In: Blood, 2010, vol. 116, n° 20, p. 4262–4273. doi: 10.1182/blood-2010-02-269837
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ISSN of the journal0006-4971
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