c-Myc primed mitochondria determine cellular sensitivity to TRAIL-induced apoptosis.
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.
Nieminen
Anni I
AI
Cancer Cell Circuitry Laboratory, Institute of Biomedicine/Biochemistry and Molecular Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Partanen
Johanna I
JI
Hau
Annika
A
Klefstrom
Juha
J
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D053181:Caspase 8 / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C494826:BAX protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051028:bcl-2-Associated X Protein; D053181:Caspase 8