Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner

Cell Metab. 2010 May 5;11(5):390-401. doi: 10.1016/j.cmet.2010.03.014.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Drosophila / metabolism
  • Glucose / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Mechanistic Target of Rapamycin Complex 1
  • Metformin / pharmacology*
  • Mice
  • Molecular Sequence Data
  • Monomeric GTP-Binding Proteins / metabolism*
  • Multiprotein Complexes
  • Phenformin / pharmacology
  • Proteins
  • Sequence Alignment
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / metabolism

Substances

  • Hypoglycemic Agents
  • Multiprotein Complexes
  • Proteins
  • TSC1 protein, human
  • Transcription Factors
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Metformin
  • Phenformin
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • AMP-Activated Protein Kinases
  • Monomeric GTP-Binding Proteins
  • Glucose