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Quantitative analys...
Quantitative analysis of amino acid metabolism in liver cancer links glutamate excretion to nucleotide synthesis
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- Nilsson, Avlant, 1985 (author)
- Chalmers tekniska högskola,Chalmers University of Technology
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- Haanstra, J. R. (author)
- Vrije Universiteit Amsterdam (VU)
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- Engqvist, Martin, 1983 (author)
- Chalmers tekniska högskola,Chalmers University of Technology
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- Gerding, Albert (author)
- Rijksuniversiteit Groningen,University of Groningen
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- Bakker, Barbara M. (author)
- Vrije Universiteit Amsterdam (VU),Rijksuniversiteit Groningen,University of Groningen
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- Klingmüller, Ursula (author)
- Deutsches Krebsforschungszentrum (DKFZ),German Cancer Research Center (DKFZ)
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- Teusink, B. (author)
- Vrije Universiteit Amsterdam (VU)
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- Nielsen, Jens B, 1962 (author)
- Danmarks Tekniske Universitet,Technical University of Denmark,Chalmers tekniska högskola,Chalmers University of Technology
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(creator_code:org_t)
- 2020-04-27
- 2020
- English.
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 117:19, s. 10294-10304
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Abstract
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- Many cancer cells consume glutamine at high rates; counterintuitively, they simultaneously excrete glutamate, the first intermediate in glutamine metabolism. Glutamine consumption has been linked to replenishment of tricarboxylic acid cycle (TCA) intermediates and synthesis of adenosine triphosphate (ATP), but the reason for glutamate excretion is unclear. Here, we dynamically profile the uptake and excretion fluxes of a liver cancer cell line (HepG2) and use genome-scale metabolic modeling for in-depth analysis. We find that up to 30% of the glutamine is metabolized in the cytosol, primarily for nucleotide synthesis, producing cytosolic glutamate. We hypothesize that excreting glutamate helps the cell to increase the nucleotide synthesis rate to sustain growth. Indeed, we show experimentally that partial inhibition of glutamate excretion reduces cell growth. Our integrative approach thus links glutamine addiction to glutamate excretion in cancer and points toward potential drug targets.
Subject headings
- NATURVETENSKAP -- Biologi -- Cellbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Cell Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Annan medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Other Medical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Keyword
- Flux-balance analysis
- Systems biology
- Genome-scale modeling
- Metabolic engineering
Publication and Content Type
- art (subject category)
- ref (subject category)
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Nilsson, Avlant, ...
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Haanstra, J. R.
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Engqvist, Martin ...
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Gerding, Albert
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Bakker, Barbara ...
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Klingmüller, Urs ...
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show more...
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Teusink, B.
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Nielsen, Jens B, ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Cell Biology
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Other Medical Bi ...
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Chalmers University of Technology