期刊
BLOOD
卷 116, 期 20, 页码 4262-4273出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-02-269837
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资金
- Ligue Nationale Contre le Cancer (LNCC comite de Paris, laboratoire associe)
- Institut National du Cancer (INCa)
- Fondation de France (comite leucemies)
- Association Laurette Fugain
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 met-formin, 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. (Blood. 2010;116(20):4262-4273)
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