Restoration of ASC expression sensitizes colorectal cancer cells to genotoxic stress-induced caspase-independent cell death

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an essential component of the inflammasome complex, is frequently silenced by epigenetic methylation in many tumor cells. Here, we demonstrate that restoration of ASC expression in human colorectal cancer DLD-1 cells, in which ASC is silenced by aberrant methylation, potentiated cell death mediated by DNA damaging agent. Contrarily, ASC knockdown in HT-29 cells rendered cells less susceptible to etoposide toxicity. The increased susceptibility of ASC-expressing DLD-1 cells to genotoxic stress was independent of inflammasome or caspase activation, but partially dependent on mitochondrial ROS production and JNK activation. Thus, our data suggest that ASC expression in cancer cells is an important factor in determining their susceptibility to chemotherapy.

► ASC expression is regulated by epigenetic methylation in colorectal cancer DLD-1 cells.
► Restoration of ASC expression in DLD-1 cells potentiated cell death in response to genotoxic stress.
► Knockdown of ASC expression in HT-29 cells attenuated etoposide-mediated cell death.
► ASC mediates ROS production and JNK activation leading to caspase-independent cell death of colorectal cancer cells.