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The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4
Open accessAbstract
Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation, and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high mTORC1 signaling may be an effective therapeutic approach.
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“mTORC1, which is well known for its function at the center of cancer metabolic reprogramming, promotes mitochondrial glutaminolysis via the migration of SIRT4-mediated inhibition of GLUD1189.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [189]
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“SIRT4 likewise appears to control tumorigenesis ((Jeong et al. 2013), (Csibi et al. 2013)) by inhibiting the high rate of glutamine metabolism associated with cancer growth;”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Csibi et al. 2013
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Metadata
- Authors
- Csibi, A., Fendt, S.-M., Li, C., Poulogiannis, G., Choo, A. Y., Chapski, D. J., Jeong, S. M., Dempsey, J. M., Parkhitko, A., Morrison, T., Henske, E. P., Haigis, M. C., Cantley, L. C., Stephanopoulos, G., Yu, J., & Blenis, J.
- Affiliations
- Harvard University (US)
- Massachusetts Institute of Technology (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Blenis, John
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 153
- Issue
- 4
- Pages
- 840-854
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3684628
- OpenAlex
- W2033228549
- Cited by
- 586
- References
- 59
- Citations by year
- 2026: 16 · 2025: 23 · 2024: 52 · 2023: 37 · 2022: 47 · 2021: 42 · 2020: 49 · 2019: 48 · 2018: 48 · 2017: 46 · 2016: 55 · 2015: 56 · 2014: 52 · 2013: 13
- FWCI
- 26.30
- Type
- journal article
- Language
- en
- Update notices
- erratum (2021-04-15)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Glenn Foundation for Medical Research
- Pfizer
- University of Pennsylvania
- Johns Hopkins University
- Life Sciences Research Foundation
- National Research Foundation
- Deutsche Forschungsgemeinschaft
- Fondation pour la Recherche Médicale
- National Research Foundation of Korea
- National Institutes of Health
- National Institute on Aging (R01AG032375, AG032375)
- National Heart, Lung, and Blood Institute (R01HL098216, R01HL121266, HL098216)
- National Cancer Institute (R01CA160458)
- National Institute of General Medical Sciences (GM51405, R01GM051405)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- mTORC1, SIRT4, glutamine metabolism, glutamine anaplerosis, glutamate dehydrogenase, ATF4, proteasomal degradation, cell proliferation, cancer metabolism, nutrient metabolism, tumor suppression, TCA cycle
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Tuberous Sclerosis Complex 2 Protein, Animals, Embryo, Mammalian, Energy Metabolism, Glutamate Dehydrogenase, Glutamine, Humans, Neoplasm Transplantation, Neoplasms, Transcription, Genetic, Transplantation, Heterologous, Mitochondrial Proteins, Tumor Suppressor Proteins, Sirtuins, Multiprotein Complexes, Cell Proliferation, Mice, Activating Transcription Factors, Ubiquitination, TOR Serine-Threonine Kinases
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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