Agents that Regulate DR5 and Sensitivity to TRAIL

Abstract

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein and a member of the TNF gene superfamily, which was identified and cloned based on sequence homology to Fas and TNF [1, 2]. TRAIL interacts with two pro-apoptotic death receptors, DR5 and DR4 (also called TRAIL-R2 and TRAIL-R1), and two decoy receptors, DcR1 and DcR2 (also called TRAIL-R3 and TRAIL-R4) [3]. DR5 and DR4 contain an intracellular death domain. As shown in Fig. 4.1, interaction of TRAIL causes trimerization of the receptors, and the activated pro-apoptotic receptors bind to an adapter protein called the Fasassociated death domain (FADD) between death domains of receptors and FADD. FADD interacts with pro-caspase-8 or -10 and forms death-inducing signaling complex (DISC), which leads to the cleavage and activation of pro-caspase-8 or -10. In type I cells, the activated caspase-8/-10 triggers apoptosis via the activation of effector caspase-3 [4]; however, in type II cells, an amplification loop through the mitochondrial pathway is required for apoptosis. Activated caspase-8 cleaves Bid, and the truncated Bid (tBid) releases cytochrome C and Smac from mitochondria to cytosol via Bax and Bak. Bcl-2 and Bcl-xL are anti-apoptotic factors inhibiting cytochrome C release. The released cytochrome C forms a complex including Apaf-1 and caspase-9, and leads to the activation of caspase-9, which consequently activates caspase-3 and induces apoptosis. IAP, XIAP, and survivin block apoptosis by inhibiting the activities of caspase-3 and -9. On the other hand, Smac released from mitochondria inhibits the action of these members of the IAP family and acts as a pro-apoptotic protein. In contrast, DcR1 does not contain an intracellular death domain and DcR2 contains a truncated death domain. These two decoy receptors are unable to transmit death signaling and act as anti-apoptotic receptors by competing with DR5 and DR4 for TRAIL interaction. TRAIL induces apoptosis selectively in cancer cells in vitro and in vivo, with little or no toxicity in normal cells [5–7]; therefore, TRAIL is one of the most promising new candidates for cancer therapeutics, although many types of cancer cells remain resistant to TRAIL [8]. Thus, to overcome resistance to TRAIL and to use TRAIL as a more powerful tool for cancer treatment, agents that can sensitize cancer cells to TRAIL play an important role. As one strategy to resolve this issue, many DR5 inducers have been discovered.