Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner
Open accessAbstract
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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Metformin directly inhibits mTORC1 via Rag-GTPase inhibition and indirectly via REDD1 upregulation promoting TSC2 activity and AMPK-mediated phosphorylation of S6K1 and 4E-BP1, decreasing translation.
“Metformin is shown to directly inhibit mTORC1 via Rag-GTPase inhibition and indirectly via REDD1 upregulation promoting TSC2 activity and AMPK activation-mediated phosphorylation of S6K1 and 4E-BP1- mTORC1 substrates decreasing its translation”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Kalender et al. 2010
Metformin's AMPK-independent mechanisms directly activate SIRT1, directly inhibit mTORC1 via Rag-GTPases, suppress adipogenesis through p70S6K inhibition, activate DNA damage-like response via ATM/Chk2, and activate Nrf2, resulting in downregulation of inflammatory responses.
“Metformin’s AMPK-independent mechanisms also contribute to the direct activation of SIRT1, direct inhibition of mTORC1 via Rag-GTPases, suppression of adipogenesis through inhibition of p70S6K pathway, activation of DNA damage-like response via the activation of ATM/Chk2 pathway, and activation of Nuclear factor erythroid 2-Related Factor 2 (Nrf2), all of which result in downregulation of”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Kalender et al. 2010
AMPK is not required for the action of metformin on cancer cells.
“it is in line with reports showing that AMPK is not required for the action of metformin on cancer cells (Kalender et al., 2010; Quinn et al., 2013).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Kalender et al., 2010
Beneficial effects of metformin are not seen in all cancers.
“In conclusion, since beneficial effects of metformin are not seen in all cancers further studies are required to determine whether the anti-cancer actions are direct or are secondary to the positive effects of metformin on healthspan that are apparent in obese patients such as improved glucose homeostasis, enhanced insulin sensitivity and reduced signaling through the IGF-1–mTOR pathway (114, 242)”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [242]
A logical target whereby metformin could mediate its putative antiproliferative effects in cancer is via inhibition of mTOR and pS6K, either via activation of AMPK or via an AMPK-independent pathway.
“A logical target whereby metformin could mediate its putative antiproliferative effects in cancer is via inhibition of mTOR and the serine-threonine kinase, ribosomal S6K (pS6K), either via activation of AMPK or via an AMPK-independent pathway (241, 242).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [242]
mTOR is a key integrator of growth factor and nutrient signals and a critical mediator of the PI3K/PKB/Akt pathway, one of the most frequently dysregulated signaling pathways in human cancer.
“The mTOR is a key integrator of growth factor and nutrient signals as well as a critical mediator of the PI3K/PKB/Akt pathway, one of the most frequently disregulated signaling pathways in human cancer [144].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [144]
Activation of AMPK leads to inhibition of mTOR through phosphorylation and subsequent activation of the tumor suppressor tuberous sclerosis complex 2.
“Activation of AMPK leads to inhibition of mTOR through phosphorylaton and subsequent activation of the tumor suppressor tuberous sclerosis complex 2 (TSC2).”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [144]
When compared to those on other treatments, metformin users had a lower risk of cancer, and a dose-relationship has been reported.
“When compared to those on other treatments, metformin users had a lower risk of cancer. A dose-relationship has been reported [138,144,145].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [144]
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- Authors
- Kalender, A., Selvaraj, A., Kim, S. Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B. E., Bardeesy, N., Dennis, P., Schlager, J. J., Marette, A., Kozma, S. C., & Thomas, G.
- Affiliations
- University of Cincinnati (US)
- Dana-Farber Cancer Institute (US)
- Université Laval (CA)
- The University of Melbourne (AU)
- Massachusetts General Hospital (US)
- United States Air Force Research Laboratory (US)
- Corresponding author
- Thomas, George
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2010-05
- Volume
- 11
- Issue
- 5
- Pages
- 390-401
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3081779
- OpenAlex
- W1998771362
- Cited by
- 889
- References
- 64
- Citations by year
- 2026: 39 · 2025: 48 · 2024: 31 · 2023: 51 · 2022: 45 · 2021: 72 · 2020: 79 · 2019: 41 · 2018: 56 · 2017: 57 · 2016: 50 · 2015: 64 · 2014: 71 · 2013: 56 · 2012: 61
- FWCI
- 24.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Canadian Institutes of Health Research
- National Cancer Institute (U01CA084292, U01CA141464)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK078019, DK73802, R01DK078019, R01DK073802)
- Air Force Research Laboratory
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- metformin, mTORC1 signaling, AMPK-independent mechanism, Rag GTPases, biguanides, phenformin, TSC1/2, AMP/ATP ratio, cancer, diabetes mellitus
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Amino Acid Sequence, Animals, Cell Line, Drosophila, Glucose, Hypoglycemic Agents, Metformin, Molecular Sequence Data, Phenformin, Proteins, Transcription Factors, Signal Transduction, Sequence Alignment, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, Multiprotein Complexes, Mice, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases
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