c-FLIP and resistance to TRAIL-induced apoptosis in pancreatic cancer

Currently, pancreatic cancer is one of the most lethal of malignant tumors due to its aggressive local behavior, rapid progress and its resistance to conventional radiation therapy and chemotherapy. No effective therapy currently exists to treat pancreatic cancers. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce apoptosis in cancer cells but does not affect normal cells supporting its role as an anti-cancer agent. However, many human pancreatic cancer cells are resistant to TRAIL. In this study we investigate the molecular basis of TRAIL resistance in pancreatic cancers. We found that the death-inducing signaling complex (DISC) is the critical regulator of TRAIL-induced apoptosis signalling, and modulation of the DISC by c-FLIP is a critical upstream event in this process. Anti-cancer agents such as cisplatin, camptothecin and celecoxib can inhibit c-FLIP-mediated cell survival signalling pathways thus overcoming TRAIL-resistance in pancreatic cancers. These findings may lead to more effective therapy for pancreatic cancer in the clinic.