Quantitative analysis of amino acid metabolism in liver cancer links glutamate excretion to nucleotide synthesis
Journal article, 2020
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.
Flux-balance analysis
Systems biology
Genome-scale modeling
Metabolic engineering
Author
Avlant Nilsson
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
J. R. Haanstra
Vrije Universiteit Amsterdam
Martin Engqvist
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Albert Gerding
University of Groningen
Barbara M. Bakker
Vrije Universiteit Amsterdam
University of Groningen
Ursula Klingmüller
German Cancer Research Center (DKFZ)
B. Teusink
Vrije Universiteit Amsterdam
Jens B Nielsen
Technical University of Denmark (DTU)
Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology
Proceedings of the National Academy of Sciences of the United States of America
0027-8424 (ISSN) 1091-6490 (eISSN)
Vol. 117 19 10294-10304Subject Categories
Cell Biology
Other Medical Biotechnology
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
DOI
10.1073/pnas.1919250117