Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion

Mol Cell. 2014 Oct 23;56(2):205-218. doi: 10.1016/j.molcel.2014.08.018. Epub 2014 Sep 18.


Many cancer cells consume large quantities of glutamine to maintain TCA cycle anaplerosis and support cell survival. It was therefore surprising when RNAi screening revealed that suppression of citrate synthase (CS), the first TCA cycle enzyme, prevented glutamine-withdrawal-induced apoptosis. CS suppression reduced TCA cycle activity and diverted oxaloacetate, the substrate of CS, into production of the nonessential amino acids aspartate and asparagine. We found that asparagine was necessary and sufficient to suppress glutamine-withdrawal-induced apoptosis without restoring the levels of other nonessential amino acids or TCA cycle intermediates. In complete medium, tumor cells exhibiting high rates of glutamine consumption underwent rapid apoptosis when glutamine-dependent asparagine synthesis was suppressed, and expression of asparagine synthetase was statistically correlated with poor prognosis in human tumors. Coupled with the success of L-asparaginase as a therapy for childhood leukemia, the data suggest that intracellular asparagine is a critical suppressor of apoptosis in many human tumors.

Publication types

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

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Apoptosis / genetics*
  • Asparagine / biosynthesis
  • Asparagine / chemistry
  • Asparagine / metabolism*
  • Aspartate-Ammonia Ligase / antagonists & inhibitors*
  • Aspartate-Ammonia Ligase / biosynthesis
  • Aspartic Acid / biosynthesis
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Citrate (si)-Synthase / genetics*
  • Citric Acid Cycle
  • Glutamine / deficiency*
  • Humans
  • Oxaloacetic Acid / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2-Associated X Protein / genetics


  • ATF4 protein, human
  • BAK1 protein, human
  • BAX protein, human
  • RNA, Small Interfering
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • Glutamine
  • Activating Transcription Factor 4
  • Oxaloacetic Acid
  • Aspartic Acid
  • Asparagine
  • Citrate (si)-Synthase
  • Aspartate-Ammonia Ligase