Glutamine Anabolism Plays a Critical Role in Pancreatic Cancer by Coupling Carbon and Nitrogen Metabolism

Cell Rep. 2019 Oct 29;29(5):1287-1298.e6. doi: 10.1016/j.celrep.2019.09.056.


Glutamine is thought to play an important role in cancer cells by being deaminated via glutaminolysis to α-ketoglutarate (aKG) to fuel the tricarboxylic acid (TCA) cycle. Supporting this notion, aKG supplementation can restore growth/survival of glutamine-deprived cells. However, pancreatic cancers are often poorly vascularized and limited in glutamine supply, in alignment with recent concerns on the significance of glutaminolysis in pancreatic cancer. Here, we show that aKG-mediated rescue of glutamine-deprived pancreatic ductal carcinoma (PDAC) cells requires glutamate ammonia ligase (GLUL), the enzyme responsible for de novo glutamine synthesis. GLUL-deficient PDAC cells are capable of the TCA cycle but defective in aKG-coupled glutamine biosynthesis and subsequent nitrogen anabolic processes. Importantly, GLUL expression is elevated in pancreatic cancer patient samples and in mouse PDAC models. GLUL ablation suppresses the development of KrasG12D-driven murine PDAC. Therefore, GLUL-mediated glutamine biosynthesis couples the TCA cycle with nitrogen anabolism and plays a critical role in PDAC.

Keywords: K-Ras; glutamate ammonia ligase; glutamine; glutamine synthetase; hexosamine; nitrogen metabolism; nucleotide; pancreatic cancer; α-ketoglutarate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon / metabolism*
  • Carcinoma, Pancreatic Ductal / enzymology
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Female
  • Gene Deletion
  • Glutamate-Ammonia Ligase / antagonists & inhibitors
  • Glutamate-Ammonia Ligase / metabolism
  • Glutamine / metabolism*
  • Humans
  • Ketoglutaric Acids / metabolism
  • Male
  • Mice, Inbred C57BL
  • Nitrogen / metabolism*
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology


  • Ketoglutaric Acids
  • Glutamine
  • Carbon
  • Glutamate-Ammonia Ligase
  • Nitrogen