c-Myc primed mitochondria determine cellular sensitivity to TRAIL-induced apoptosis

EMBO J. 2007 Feb 21;26(4):1055-67. doi: 10.1038/sj.emboj.7601551. Epub 2007 Feb 1.


Oncogenic c-Myc renders cells sensitive to TRAIL-induced apoptosis, and existing data suggest that c-Myc sensitizes cells to apoptosis by promoting activation of the mitochondrial apoptosis pathway. However, the molecular mechanisms linking the mitochondrial effects of c-Myc to the c-Myc-dependent sensitization to TRAIL have remained unresolved. Here, we show that TRAIL induces a weak activation of procaspase-8 but fails to activate mitochondrial proapoptotic effectors Bax and Bak, cytochrome c release or downstream effector caspase-3 in non-transformed human fibroblasts or mammary epithelial cells. Our data is consistent with the model that activation of oncogenic c-Myc primes mitochondria through a mechanism involving activation of Bak and this priming enables weak TRAIL-induced caspase-8 signals to activate Bax. This results in cytochrome c release, activation of downstream caspases and postmitochondrial death-inducing signaling complex -independent augmentation of caspase-8-Bid activity. In conclusion, c-Myc-dependent priming of the mitochondrial pathway is critical for the capacity of TRAIL-induced caspase-8 signals to activate effector caspases and for the establishment of lethal caspase feedback amplification loop in human cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Blotting, Western
  • Caspase 8 / metabolism
  • Cell Line
  • Humans
  • Microscopy, Fluorescence
  • Mitochondria / metabolism*
  • Models, Biological
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • TNF-Related Apoptosis-Inducing Ligand / genetics*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • bcl-2-Associated X Protein / metabolism


  • BAX protein, human
  • MYC protein, human
  • Proto-Oncogene Proteins c-myc
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • bcl-2-Associated X Protein
  • Caspase 8