Abstract 4852: cFLIP-regulated and caspase-8-mediated limited cleavage of RIP1 promotes NF-kB activation and inhibits cell death induced by TRAIL

Although TRAIL is considered a potential anti-cancer agent, many types of cancer cells possess intrinsic or acquired resistance to TRAIL. In addition, TRAIL has been found to activate NF-κB and enhance metastasis in apoptosis-resistant cancer cells. Notably, caspase-8 activity and RIP1 expression have been shown to be essential for TRAIL-induced NF-κB activation. RIP1 is a dual-function molecule that can be either prosurvival or prodeath depending on the cellular context. RIP1 contains an N-terminal kinase domain (KD), a C-terminal death domain (DD) and an intermediate domain (ID) between the KD and DD domains. The ID domain of RIP1 is essential for its activation of the NF-κB pathway, whereas the KD domain is required for its induction of apoptosis and necrosis. We have discovered that, in apoptosis-sensitive cells, caspase-8 cleaves RIP1 in the KD and ID domains in response to TRAIL treatment, resulting in rapid depletion of RIP1 and the induction of apoptosis. In apoptosis-resistant cells, however, cFLIP inhibited caspase-8-mediated RIP1 cleavage in the ID but not in the KD domain, producing a KD domain-deleted C-terminal fragment, p51RIP1c. Stable expression of p51RIP1c in RIP1−/− cells significantly promoted NF-κB activation and inhibited cell death induced by TRAIL. Moreover, stable expression of the cleavage sites-mutated form of RIP1 in RIP1−/− cells, not only sensitized the cells to apoptosis induced by TRAIL, but also to necrosis induced by oxidative stress. Importantly, in Hodgkin's lymphomas that overexpress cFLIP, as well as in tumor tissues derived from iMyc-Bcl-XL double transgenic mice, a portion of RIP1 is constitutively processed to p51RIP1c. Collectively, these data suggest that cFLIP-regulated and caspase-8-mediated limited cleavage of RIP1 promotes NF-κB activation and inhibits cell death, and that such cleavage occurs constitutively in certain types of cancers. Thus, inhibiting cFLIP-regulated RIP1 cleavage could be a new target for maximizing the effectiveness of TRAIL as an anti-cancer agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4852. doi:1538-7445.AM2012-4852