Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells

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

doi:10.1016/j.cmet.2016.03.016

Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells

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

Research output: Contribution to journal › Article › peer-review

218 Citations (Scopus)

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.

Original language	English
Pages (from-to)	867-880
Number of pages	14
Journal	Cell Metabolism
Volume	23
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2016.03.016
Publication status	Published - May 10 2016
Externally published	Yes

Bibliographical note

Funding Information:
We thank Grace Gao, Marcin Iwanicki, Lisa Gallegos, Cheuk Leung, Taru Muranen, Angie Martinez Gakidis, John Blenis, Jessica Spinelli, Marcia Haigis, and Brandon Nicolay for reagents and/or helpful discussions. Images were acquired at The Nikon Imaging Center at Harvard Medical School. PAM50 subtype calls for the TCGA data were generously provided by Charles Perou. This research was supported by Roche Pharmaceuticals (J.S.B.) and a fellowship from the American Cancer Society (J.L.C.).

Publisher Copyright:
© 2016 Elsevier Inc.

ASJC Scopus Subject Areas

Physiology
Molecular Biology
Cell Biology

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2016.03.016

Cite this

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title = "Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells",

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.",

author = "Coloff, {Jonathan L.} and Murphy, {J. Patrick} and Braun, {Craig R.} and Harris, {Isaac S.} and Shelton, {Laura M.} and Kenjiro Kami and Gygi, {Steven P.} and Selfors, {Laura M.} and Brugge, {Joan S.}",

note = "Funding Information: We thank Grace Gao, Marcin Iwanicki, Lisa Gallegos, Cheuk Leung, Taru Muranen, Angie Martinez Gakidis, John Blenis, Jessica Spinelli, Marcia Haigis, and Brandon Nicolay for reagents and/or helpful discussions. Images were acquired at The Nikon Imaging Center at Harvard Medical School. PAM50 subtype calls for the TCGA data were generously provided by Charles Perou. This research was supported by Roche Pharmaceuticals (J.S.B.) and a fellowship from the American Cancer Society (J.L.C.). Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

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AU - Kami, Kenjiro

AU - Gygi, Steven P.

AU - Selfors, Laura M.

AU - Brugge, Joan S.

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N2 - 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.

AB - 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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Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

UN SDGs

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