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

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Abstract
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.