Of these two molecules, Smac is the most important for TRAIL's activity. The primary function of released cyt c is the activation of caspase 9, but Wu found that caspase 9 was not required for TRAIL-dependent apoptosis. In contrast, cytosolic Smac could overcome the requirement for Bax.
Once in the cytosol, Smac appears to displace XIAP from caspase 3, allowing the final maturation of caspase 3 that was begun by caspase 8. With XIAP levels high in some cancer cells, additional activation of the mitochondrial pathway (e.g., by DNA-damaging agents) may help TRAIL to kill these cells. ▪