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Cell Metab. 2016 May 10;23(5):867-80. doi: 10.1016/j.cmet.2016.03.016. Epub 2016 Apr 28.

Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells.

Author information

1
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
2
Human Metabolome Technologies America, Boston, MA 02134, USA.
3
Human Metabolome Technologies, Tsuruoka, 997-0052 Japan.
4
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: joan_brugge@hms.harvard.edu.

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.

PMID:
27133130
DOI:
10.1016/j.cmet.2016.03.016
[Indexed for MEDLINE]
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