Fig. 4.

TRAIL-induced apoptosis signaling pathway. TRAIL initiates apoptosis through binding to DR4 and/or DR5. TRAIL binding induces receptor trimerization to promote the assembly of DISC (composed of FADD and procaspases 8/10) to induce self-cleavage and thus activation of caspases 8/10, which in turn trigger downstream caspase cascade to execute apoptosis program. In certain cell types, activated caspase 8 cleaves BID to generate truncated BID (tBID), which in turn triggers the mitochondrial apoptosis pathway. c-FLIP competes with procaspase 8 for recruitment to DISC, thereby suppressing activation of procaspase 8 and thus dampening TRAIL-initiated apoptosis stimuli. Antiapoptotic BCL-2 family members BCL-2, BCL-xL, and MCL-1 suppress the activation of the mitochondrial apoptosis pathway to blunt TRAIL-induced apoptosis. IAP proteins survivin and XIAP induce TRAIL resistance via the blockade of the activity of executioner caspases.