Cited by 587PI3K/AKT/mTOR signaling in cancerCancer, Hypoxia, and MetabolismSirtuins and Resveratrol in Medicine

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The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4

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Csibi, Alfred, Fendt, Sarah-Maria, Li, Chenggang, Poulogiannis, George, Choo, Andrew Y., Chapski, Douglas J., Jeong, Seung Min, Dempsey, Jamie M., Parkhitko, Andrey, Morrison, Tasha, Henske, Elizabeth P., Haigis, Marcia C., Cantley, Lewis C., Stephanopoulos, Gregory, Yu, Jane, Blenis, John·2013·Cell

DOI 10.1016/j.cell.2013.04.023PMC PMC3684628

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Abstract

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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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: Fendt, Sarah-Maria
Li, Chenggang
Poulogiannis, George
Chapski, Douglas J.
Jeong, Seung Min
Parkhitko, Andrey
Morrison, Tasha
Henske, Elizabeth P.
Haigis, Marcia C.
Cantley, Lewis C.
Stephanopoulos, Gregory
Yu, Jane
Blenis, John
Venue: Cell
Publisher: Elsevier BV
Published: 2013-05
Volume: 153
Issue: 4
Pages: 840-854
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2013.04.023
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 373 d)
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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The mTORC1 Pathway Stimulates Glutamine Metabolism and Cell Proliferation by Repressing SIRT4

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