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

Ji Zhang, Jing Fan, Sriram Venneti, Justin R. Cross, Toshimitsu Takagi, Bhavneet Bhinder, Hakim Djaballah, Masayuki Kanai, Emily H. Cheng, Alexander R. Judkins, Bruce Pawel, Julie Baggs, Sara Cherry, Joshua D. Rabinowitz, Craig B. Thompson

Research output: Contribution to journalArticle

152 Scopus citations

Abstract

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-withdrawalinduced 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.

Original languageEnglish (US)
Pages (from-to)205-218
Number of pages14
JournalMolecular Cell
Volume56
Issue number2
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Zhang, J., Fan, J., Venneti, S., Cross, J. R., Takagi, T., Bhinder, B., Djaballah, H., Kanai, M., Cheng, E. H., Judkins, A. R., Pawel, B., Baggs, J., Cherry, S., Rabinowitz, J. D., & Thompson, C. B. (2014). Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Molecular Cell, 56(2), 205-218. https://doi.org/10.1016/j.molcel.2014.08.018