The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation
Open accessAbstract
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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Animal experiments have elucidated the mechanisms underlying these epidemiological findings, i.e., interference with glucose, protein, and lipid metabolism of the neoplastic cells.
“and interference with glucose(266), protein(267, 268), and lipid(269) metabolism of the neoplastic cells.”
From Metformin, the Aspirin of the 21st Century: Its Role in Gestational Diabetes Mellitus, Prevention of Preeclampsia and Cancer, and the Promotion of Longevity (2017) · cites this paper as [267]
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- Authors
- Green, A. S., Chapuis, N., Trovati Maciel, T., Willems, L., Lambert, M., Arnoult, C., Boyer, O., Bardet, V., Park, S., Foretz, M., Viollet, B., Ifrah, N., Dreyfus, F., Hermine, O., Cruz Moura, I., Lacombe, C., Mayeux, P., Bouscary, D., & Tamburini, J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm U699, Faculté de Médecine Xavier Bichat, Paris, France;
- Centre Hospitalier Universitaire de Rouen (FR)
- Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France;
- Centre Hospitalier Universitaire d'Angers (FR)
- Hôpital Necker-Enfants Malades (FR)
- Corresponding author
- Chapuis, Nicolas
- Bouscary, Didier
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2010-11-18
- Volume
- 116
- Issue
- 20
- Pages
- 4262-4273
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2146788325
- Cited by
- 199
- References
- 49
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 8 · 2023: 8 · 2022: 8 · 2021: 12 · 2020: 16 · 2019: 11 · 2018: 15 · 2017: 14 · 2016: 9 · 2015: 27 · 2014: 19 · 2013: 16 · 2012: 14
- FWCI
- 5.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- HAL (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- Ligue Contre le Cancer
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- acute myeloid leukemia, LKB1, AMPK, mTOR, metformin, 4E-BP1, mRNA translation, tumor suppressor pathways, antileukemic activity, biguanides, polysome recruitment, targeted therapy
- MeSH terms
- Tuberous Sclerosis Complex 2 Protein, AMP-Activated Protein Kinase Kinases, Animals, Enzyme Activation, Hematopoietic Stem Cells, Humans, Metformin, Neoplasm Proteins, Phosphoproteins, Phosphorylation, Polyribosomes, Protein Kinases, Protein Biosynthesis, Signal Transduction, Leukemia, Myeloid, Acute, Cell Death, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Tumor Suppressor Proteins, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Biocatalysis, TOR Serine-Threonine Kinases
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