Quantitative analysis of amino acid metabolism in liver cancer links glutamate excretion to nucleotide synthesis

Avlant Nilsson, Jurgen R. Haanstra, Martin Engqvist, Albert Gerding, Barbara M. Bakker, Ursula Klingmueller, Bas Teusink, Jens Nielsen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)
22 Downloads (Pure)

Abstract

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.

Original languageEnglish
Pages (from-to)10294-10304
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number19
DOIs
Publication statusPublished - 12-May-2020

Keywords

  • genome-scale modeling
  • flux-balance analysis
  • systems biology
  • metabolic engineering
  • FLUX BALANCE ANALYSIS
  • HEPATOCELLULAR-CARCINOMA
  • CYSTINE/GLUTAMATE ANTIPORTER
  • IDENTIFICATION
  • SULFASALAZINE
  • TRANSPORTER
  • REVEALS
  • GROWTH
  • CELLS
  • CHROMATOGRAPHY

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