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

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

Author information

1
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
3
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
High-Throughput Screening Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, USA.
7
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
9
Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
10
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: thompsonc@mskcc.org.

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-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.

PMID:
25242145
PMCID:
PMC4224619
DOI:
10.1016/j.molcel.2014.08.018
[Indexed for MEDLINE]
Free PMC Article

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