Polyphenols Isolated from Propolis Augment TRAIL-Induced Apoptosis in Cancer Cells
TRAIL-induced apoptotic pathways in cancer cells. TRAIL binds to death receptors, TRAIL-R1 and/or TRAIL-R2 and promotes the recruitment of adaptor molecule FADD (Fas-associated-death domain) to activate caspase-8 and/or caspase-10, which trigger activation of downstream effector caspases (caspase-3, -6, -7). FLIP can block activation of caspase-8 or casapase-10. Caspase-8 mediated also cleavage of Bid (BH3-interacting domain death agonist). Trucated Bid called tBid translocates to the mitochondria where it interacts with proapoptotic Bax and Bak, stimulating disruption of MMP (mitochondrial membrane potential) and the release of cytochrome c and Smac/DIABLO (second mitochondrial activator of caspases/direct inhibitor of apoptosis binding protein with low isoelectric point). Antiapoptotic members of Bcl-2 family (Bcl-2, Bcl-xL, and Mcl-1) could inhibit loss of MMP. Akt may prevent cytochrome c escape to cytosol. Cytochrome c liberated from the mitochondria binds to the adaptor protein Apaf-1 (apoptotic protease-activating factor-1) and procaspase-9, forming the apoptosome and activating caspase-9 which in turn activates executioner caspases (caspase-3, -6, -7) leading to cell death. Activity of executioner caspases is inhibited by IAPs (inhibitor of apoptosis protein): IAP-1, IAP-2, XIAP, and survivin. Smac/DIABLO blocks IAPs.