title: ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.
abstract: Oncogenic Myc alters mitochondrial metabolism, making it dependent on exogenous glutamine (Gln) for cell survival. Accordingly, Gln deprivation selectively induces apoptosis in MYC-overexpressing cells via unknown mechanisms. Using MYCN-amplified neuroblastoma as a model, we identify PUMA, NOXA, and TRB3 as executors of Gln-starved cells. Gln depletion in MYC-transformed cells induces apoptosis through ATF4-dependent, but p53-independent, PUMA and NOXA induction. MYC-transformed cells depend on both glutamate-oxaloacetate transaminase and glutamate dehydrogenase to maintain Gln homeostasis and suppress apoptosis. Consequently, either ATF4 agonists or glutaminolysis inhibitors potently induce apoptosis in vitro and inhibit tumor growth in vivo. These results reveal mechanisms whereby Myc sensitizes cells to apoptosis, and validate ATF4 agonists and inhibitors of Gln metabolism as potential Myc-selective cancer therapeutics.
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Qing
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Annette
authors.initials: A
authors.lastname: Vu
authors.forename: Nicolas
authors.initials: N
authors.lastname: Skuli
authors.forename: Zandra E
authors.initials: ZE
authors.lastname: Walton
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Liu
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Mayes
authors.forename: David R
authors.initials: DR
authors.lastname: Wise
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Michael D
authors.initials: MD
authors.lastname: Hogarty
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C438378:BBC3 protein, human; D018797:Cell Cycle Proteins; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D005973:Glutamine; D051701:Activating Transcription Factor 4; D000625:Aminooxyacetic Acid; D017346:Protein Serine-Threonine Kinases; D020169:Caspases