RESUMEN

Smac mimetic compounds (SMCs) potentiate TNFα-mediated cancer cell death by targeting the inhibitor of apoptosis (IAP) proteins. In addition to TNFα, the tumor microenvironment is exposed to a number of pro-inflammatory cytokines, including IL-1ß. Here, we investigated the potential impact of IL-1ß 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-1ß treatment, which required IL-1ß-induced activation of the NF-κB pathway. Elevated NF-κB activity resulted in the production of TNFα, 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-1ß-mediated cell death. Importantly, SMC-resistant cells that produced TNFα in response to IL-1ß 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-1ß 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.

Asunto(s)

Alquinos/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Dipéptidos/farmacología , Interleucina-1beta/farmacología , Neoplasias/tratamiento farmacológico , Peptidomiméticos/farmacología , Alquinos/agonistas , Animales , Antineoplásicos/agonistas , Proteína 3 que Contiene Repeticiones IAP de Baculovirus , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/genética , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Caspasa 8/genética , Caspasa 8/metabolismo , Línea Celular Tumoral , Dipéptidos/agonistas , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Técnicas de Silenciamiento del Gen , Humanos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Interleucina-1beta/agonistas , Ratones , FN-kappa B/genética , FN-kappa B/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Peptidomiméticos/agonistas , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Ubiquitina-Proteína Ligasas