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-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.
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Venneti
authors.affiliation: Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Cross
authors.affiliation: High-Throughput Screening Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Takagi
authors.affiliation: High-Throughput Screening Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Bhavneet
authors.initials: B
authors.lastname: Bhinder
authors.affiliation: High-Throughput Screening Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Hakim
authors.initials: H
authors.lastname: Djaballah
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kanai
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Emily H
authors.initials: EH
authors.lastname: Cheng
authors.affiliation: 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.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Judkins
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Pawel
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Baggs
authors.affiliation: Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Cherry
authors.affiliation: Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: thompsonc@mskcc.org.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D001216:Asparagine / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D001217:Aspartate-Ammonia Ligase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D001224:Aspartic Acid / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002950:Citrate (si)-Synthase / Q000235:genetics*; D002952:Citric Acid Cycle; D005973:Glutamine / Q000172:deficiency*; D006801:Humans; D062907:Oxaloacetic Acid / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: C497109:ATF4 protein, human; C494772:BAK1 protein, human; C494826:BAX protein, human; D034741:RNA, Small Interfering; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D005973:Glutamine; D051701:Activating Transcription Factor 4; D062907:Oxaloacetic Acid; D001224:Aspartic Acid; D001216:Asparagine; D002950:Citrate (si)-Synthase; D001217:Aspartate-Ammonia Ligase