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

Free University of Amsterdam

Martin Engqvist

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Albert Gerding

University of Groningen

Barbara M. Bakker

Free University of Amsterdam

University of Groningen

Ursula Klingmüller

German Cancer Research Center (DKFZ)

B. Teusink

Free University of 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 10294-10304

Subject 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

More information

Latest update

6/24/2020