期刊
CELL METABOLISM
卷 11, 期 5, 页码 390-401出版社
CELL PRESS
DOI: 10.1016/j.cmet.2010.03.014
关键词
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资金
- Association Nationale de la Recherche [R06428KS]
- European Commission [LSHM-CT-2004-005272]
- National Health and Medical Research Council (NHMRC)
- Australia and the Australian Research Council (ARC)
- Canadian Institutes of Health Research (CIHR)
- National Institutes of Health (NIH) [U01 CA141464]
- NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK73802, DK078019]
- Strauss Chair in Cancer Research
Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the antidiabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2 but also in the absence of AMPK. Consistent with these observations, in two distinct preclinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.
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