Caspase 8-dependent sensitization of cancer cells to TRAIL-induced apoptosis following reovirus-infection

TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis in suscepti ble cells by binding to death receptors 4 (DR4) and 5 (DR5). TRAIL preferen tially induces apoptosis in transformed cells and the identification of mec hanisms by which TRAIL-induced apoptosis can be enhanced may lead to novel cancer chemotherapeutic strategies. Here we show that reovirus infection in duces apoptosis in cancer cell lines derived from human breast, lung and ce rvical cancers. Reovirus-induced apoptosis is mediated by TRAIL and is asso ciated with the release of TRAIL from infected cells. Reovirus infection sy nergistically and specifically sensitizes cancer cell lines to killing by e xogenous TRAIL. This sensitization both enhances the susceptibility of prev iously resistant cell lines to TRAIL-induced apoptosis and reduces the amou nt of TRAIL needed to kill already sensitive lines. Sensitization is not as sociated with a detectable change in the expression of TRAIL. receptors in reovirus-infected cells. Sensitization is associated with an increase in th e activity of the death receptor-associated initiator caspase. caspase 8, a nd is inhibited by the peptide IETD-fmk, suggesting that reovirus sensitize s cancer cells to TRAIL-induced apoptosis in a caspase 8-dependent manner. Reovirus-induced sensitization of cells to TRAIL is also associated with in creased cleavage of PARP, a substrate of the effector caspases 3 and 7.