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Linking of N-Myc to death receptor machinery in neuroblastoma cells

Hongjuan Cui1, Tai Li, Han-Fei Ding

  • 1Department of Biochemistry and Cancer Biology, Medical College of Ohio, Toledo, Ohio 43614, USA.

The Journal of Biological Chemistry
|January 6, 2005
PubMed

Insights

The oncogene N-Myc promotes neuroblastoma growth but can be targeted by death receptor pathways. N-Myc sensitizes cells to TRAIL-induced apoptosis by upregulating DR5 and Bid, offering a potential therapeutic checkpoint.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Death Pathways

Background:

  • The MYCN oncogene is amplified in aggressive neuroblastomas.
  • Caspase-8, crucial for death receptor pathways, is often inactivated in these tumors.
  • N-Myc overexpression sensitizes neuroblastoma cells to apoptosis induced by death ligands.

Purpose of the Study:

  • To elucidate the mechanism by which N-Myc sensitizes neuroblastoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis.
  • To investigate the role of death receptor signaling in N-Myc-driven neuroblastoma.

Main Methods:

  • Utilized TRAIL-induced apoptosis as a model system.
  • Analyzed caspase-8 activation, Bid cleavage, and mitochondrial protein release (cytochrome c, Smac/DIABLO) in neuroblastoma cells with varying N-Myc levels.
  • Investigated the transcriptional regulation of TRAIL receptor-2/DR5/KILLER and Bid by N-Myc.

Main Results:

  • N-Myc-overexpressing neuroblastoma cells exhibit enhanced TRAIL-induced caspase-8 activation and Bid cleavage.
  • Apoptosis induction requires Smac/DIABLO but not cytochrome c-mediated caspase-9 activation.
  • N-Myc upregulates both TRAIL receptor-2/DR5/KILLER and Bid expression.
  • N-Myc directly binds to the DR5 promoter, driving its transcription.

Conclusions:

  • N-Myc sensitizes neuroblastoma cells to TRAIL-induced apoptosis by upregulating DR5 and Bid.
  • This N-Myc-mediated sensitization involves Smac/DIABLO release and caspase-8 activation.
  • The findings establish a mechanistic link between N-Myc and death receptor signaling, highlighting a potential checkpoint against N-Myc-driven tumorigenesis.

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