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PMID: 23153536 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation.

Cancer cell ·Vol. 22 ·No. 5 ·2012-11-13 ·Pages 631-44

Qing G, Li B, Vu A, Skuli N, Walton ZE, Liu X, Mayes PA, Wise DR, Thompson CB, Maris JM, Hogarty MD, Simon MC

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.

MeSH Terms
Activating Transcription Factor 4/genetics,metabolism,physiology Aminooxyacetic Acid/pharmacology Animals Apoptosis/drug effects Apoptosis Regulatory Proteins/metabolism Caspases/metabolism Cell Cycle Proteins/metabolism Cell Proliferation/drug effects Glutamine/metabolism Humans Mice Mice, Inbred BALB C Mice, Nude Neuroblastoma/metabolism,pathology Protein Serine-Threonine Kinases/antagonists & inhibitors,metabolism Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-bcl-2/metabolism Proto-Oncogene Proteins c-myc/genetics,metabolism,physiology Repressor Proteins/metabolism Tumor Suppressor Protein p53/physiology bcl-2-Associated X Protein/metabolism
Chemicals
ATF4 protein, human Apoptosis Regulatory Proteins BAX protein, human BBC3 protein, human Cell Cycle Proteins PMAIP1 protein, human Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 Proto-Oncogene Proteins c-myc Repressor Proteins TRIB3 protein, human Tumor Suppressor Protein p53 bcl-2-Associated X Protein Glutamine Activating Transcription Factor 4 Aminooxyacetic Acid Protein Serine-Threonine Kinases Caspases
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Qing Guoliang
Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Li Bo
Vu Annette
Skuli Nicolas
Walton Zandra E
Liu Xueyuan
Mayes Patrick A
Wise David R
Thompson Craig B
Maris John M
Hogarty Michael D
Simon M Celeste
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2012.09.021
Published
2012-11-13
Pages
631-44
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3510660
Subset
IM
Grants
NCI NIH HHS · CA97323 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · CA104838 · United States
NCI NIH HHS · 1F32CA137988 · United States
NCI NIH HHS · P01 CA104838 · United States
NCI NIH HHS · P30 CA016520 · United States
NCI NIH HHS · P01 CA097323 · United States
NCI NIH HHS · CA097323 · United States
NCI NIH HHS · F32 CA137988 · United States
NCI NIH HHS · CA105463 · United States
External Links
PubMed source DOI: 10.1016/j.ccr.2012.09.021 PMC Full Text View journal details
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