@article{06d091f1abc5471281a6580de2893d87,
title = "Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion",
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.",
author = "Ji Zhang and Jing Fan and Sriram Venneti and Cross, {Justin R.} and Toshimitsu Takagi and Bhavneet Bhinder and Hakim Djaballah and Masayuki Kanai and Cheng, {Emily H.} and Judkins, {Alexander R.} and Bruce Pawel and Julie Baggs and Sara Cherry and Rabinowitz, {Joshua D.} and Thompson, {Craig B.}",
note = "Funding Information: We thank members of the Thompson laboratory, particularly Jiangbin Ye, for critical discussions and suggestions for the manuscript. We also thank the Flow Cytometry and the Molecular Cytology Core Facilities of MSKCC for their help with flow cytometry and imaging data. The HTS Core Facility is supported by Mr. William H. Goodwin and Mrs. Alice Goodwin, by the Commonwealth Foundation for Cancer Research, by the ETC of MSKCC, by the Lillian S. Wells Foundation, and by a NIH/NCI Cancer Center Support Grant P30 CA008748. J.Z. was supported by the Leukemia and Lymphoma Society fellowship. J.F. was supported by HHMI international student research fellowship. S.V. is supported by NIH K08 CA181475. This work was also supported, in part, by grants from NIH R01 CA105463, the Abramson Family Cancer Research Institute, and Memorial Sloan Kettering Cancer Center. C.B.T. is a founder of Agios Pharmaceuticals and a member of its scientific advisory board. C.B.T. also serves on the board of directors of Merck. Publisher Copyright: {\textcopyright} 2014 Elsevier Inc.",
year = "2014",
doi = "10.1016/j.molcel.2014.08.018",
language = "English (US)",
volume = "56",
pages = "205--218",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",
}