Targeting TRAIL Agonistic Receptors for Cancer Therapy

Crosstalk between apoptosis signaling pathways following activation of death receptors. Death receptors trigger the cell-intrinsic pathway by activation of caspase-8 and caspase-10. Cleaved BID interacts with Bax and Bak, which in turn, activate caspase-9 and caspase-3, resulting in apoptosis induction through the cell-extrinsic pathway. In type I cells, death-receptor engagement of the cell-extrinsic pathway is sufficient for commitment to apoptotic death. In type II cells, commitment to apoptosis requires the amplification of the death-receptor signal by the cell-intrinsic pathway. Because death-receptor targeting and conventional agents induce tumor cell apoptosis through different signaling pathways, combinations of the two approaches might facilitate the killing of tumor cells that resist death induction through either one of the pathways.