Schema for basic apoptotic signaling
pathways and possible mechanisms underlying PPAR ligand-induced apoptosis. Ligation
of death ligands (e.g., TRAIL) with their receptors (e.g., DR5) results in
formation of the death-inducing signaling complex (DISC), in which
pro-caspase-8 will be recruited through the death adaptor protein FADD and
cleaved to generate activated caspase-8. This process is inhibited by c-FLIP.
Certain stress signals (e.g., DNA damage) can target mitochondria and induce
cytochrome C release from the mitochondria into the cytosol leading to caspase-9
activation by forming an apoptosome via binding to Apaf-1. Both caspase-8 and caspase-9 activate
downstream procaspase-3, -6, and -7, leading to cleavages of their target death
proteins such as PARP. In addition, truncated Bid (tBid), activated by caspase-8
via cleavage, facilitates insertion of Bax into the mitochondrial membrane
leading to cytochrome C release. Therefore, tBid may serve as a link between
the extrinsic and intrinsic apoptotic pathways. Inhibitors of apoptosis
proteins (IAPs) such as survivin can bind to activated caspase-9 and prevent
its action on effector caspases, whereas SMAC/DIABLO binds to IAPs, leaving
caspase-9 free to activate the effector caspases. PPAR ligands may induce apoptosis through
induction of DR5 and/or downregulation of c-FLIP and/or survivin.
