Smac Mimetic Compounds Potentiate Interleukin-1β-mediated Cell Death

Smac mimetic compounds (SMCs) potentiate TNF beta-mediated cancer cell death by targeting the inhibitor of apoptosis (IAP) proteins. In addition to TNF alpha, the tumor microenvironment is exposed to a number of pro-inflammatory cytokines, including IL-1 beta. Here, we investigated the potential impact of IL-1 beta on SMC-mediated death of cancer cells. Synergy was seen in a subset of a diverse panel of 21 cancer cell lines to the combination of SMC and IL-1 beta treatment, which required IL1 beta-induced activation of the NF-kappa B pathway. Elevated NF-kappa B activity resulted in the production of TNF alpha, which led to apoptosis dependent on caspase-8 and RIP1. In addition, concurrent silencing of cIAP1, cIAP2, and X-linked IAP by siRNA was most effective for triggering IL-1 beta-mediated cell death. Importantly, SMC-resistant cells that produced TNF in response to IL-1 beta treatment were converted to an SMC-sensitive phenotype by c-FLIP knockdown. Reciprocally, ectopic expression of c-FLIP blocked cell death caused by combined SMC and IL-1 beta treatment in sensitive cancer cells. Together, our study indicates that a positive feed-forward loop by pro-inflammatory cytokines can be exploited by SMCs to induce apoptosis in cancer cells.