Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells

Coloff, Jonathan L.; Murphy, J. Patrick; Braun, Craig R.; Harris, Isaac S.; Shelton, Laura M.; Kami, Kenjiro; Gygi, Steven P.; Selfors, Laura M.; Brugge, Joan S.

doi:10.1016/j.cmet.2016.03.016

Cited by 288Amino Acid Enzymes and MetabolismCancer, Hypoxia, and MetabolismPI3K/AKT/mTOR signaling in cancer

Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells

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Coloff, Jonathan L., Murphy, J. Patrick, Braun, Craig R., Harris, Isaac S., Shelton, Laura M., Kami, Kenjiro, Gygi, Steven P., Selfors, Laura M. +1 more·2016·Cell Metabolism

DOI 10.1016/j.cmet.2016.03.016

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Abstract

Mammary epithelial cells transition between periods of proliferation and quiescence during development, menstrual cycles, and pregnancy, and as a result of oncogenic transformation. Utilizing an organotypic 3D tissue culture model coupled with quantitative metabolomics and proteomics, we identified significant differences in glutamate utilization between proliferating and quiescent cells. Relative to quiescent cells, proliferating cells catabolized more glutamate via transaminases to couple non-essential amino acid (NEAA) synthesis to α-ketoglutarate generation and tricarboxylic acid (TCA) cycle anaplerosis. As cells transitioned to quiescence, glutamine consumption and transaminase expression were reduced, while glutamate dehydrogenase (GLUD) was induced, leading to decreased NEAA synthesis. Highly proliferative human tumors display high transaminase and low GLUD expression, suggesting that proliferating cancer cells couple glutamine consumption to NEAA synthesis to promote biosynthesis. These findings describe a competitive and partially redundant relationship between transaminases and GLUD, and they reveal how coupling of glutamate-derived carbon and nitrogen metabolism can be regulated to support cell proliferation.

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Authors: Coloff, J. L., Murphy, J. P., Braun, C. R., Harris, I. S., Shelton, L. M., Kami, K., Gygi, S. P., Selfors, L. M., & Brugge, J. S.
Affiliations: Harvard University (US)
Human Metabolome Technologies, Inc. (Japan) (JP)
Corresponding author: Brugge, Joan S.
ORCID: Coloff, Jonathan L.
Murphy, J. Patrick
Harris, Isaac S.
Shelton, Laura M.
Gygi, Steven P.
Selfors, Laura M.
Brugge, Joan S.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2016-05
Volume: 23
Issue: 5
Pages: 867-880
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2016.03.016
OpenAlex: W2343650972
Cited by: 288
References: 58
Citations by year: 2026: 12 · 2025: 13 · 2024: 23 · 2023: 32 · 2022: 40 · 2021: 44 · 2020: 40 · 2019: 26 · 2018: 22 · 2017: 23 · 2016: 12
FWCI: 18.27
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 374 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
IslandScholar (University of Prince Edward Island) (submittedVersion)
Funders: National Cancer Institute (P30CA016672)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords: glutamate metabolism, mammary epithelial cells, cell proliferation, quiescent cells, transaminases, glutamate dehydrogenase, glutamine consumption, alpha-ketoglutarate, TCA cycle anaplerosis, mammary tumors
MeSH terms: Transaminases, Breast Neoplasms, Cells, Cultured, Epithelial Cells, Female, Glutamate Dehydrogenase, Humans, Models, Biological, Nitrogen Isotopes, Signal Transduction, Glutamic Acid, Phosphatidylinositol 3-Kinases, Proteomics, Mammary Glands, Human, Cell Proliferation, Proto-Oncogene Proteins c-akt, Metabolomics, TOR Serine-Threonine Kinases

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Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells

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