ATF4 regulates MYC-mediated neuroblastoma cell death upon glutamine deprivation

Cancer Cell. 2012 Nov 13;22(5):631-44. doi: 10.1016/j.ccr.2012.09.021.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Activating Transcription Factor 4 / physiology*
  • Aminooxyacetic Acid / pharmacology
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis* / drug effects
  • Caspases / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation / drug effects
  • Glutamine / metabolism*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neuroblastoma / metabolism*
  • Neuroblastoma / pathology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Proto-Oncogene Proteins c-myc / physiology*
  • Repressor Proteins / metabolism
  • Tumor Suppressor Protein p53 / physiology
  • bcl-2-Associated X Protein / metabolism

Substances

  • 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