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Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia

2015; Cell Press; Volume: 11; Issue: 9 Linguagem: Inglês

10.1016/j.celrep.2015.04.063

2639-1856

Pierre Sujobert, Laury Poulain, Étienne Paubelle, Florence Zylbersztejn, Adrien Grenier, Mireille Lambert, Elizabeth C. Townsend, Jean‐Marie Brusq, Edwige Nicodème, Justine Decrooqc, Ina Nepstad, Alexa S. Green, Johanna Mondésir, Marie‐Anne Hospital, Nathalie Jacque, Alexandra Christodoulou, Tiffany DeSouza, Olivier Hermine, Marc Foretz, Benoı̂t Viollet, Catherine Lacombe, Patrick Mayeux, David M. Weinstock, Ivan Cruz Moura, Didier Bouscary, Jérôme Tamburini,

PI3K/AKT/mTOR signaling in cancer

AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers.