Abstract
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-1β. Here, we investigated the potential impact of IL-1β 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-1β treatment, which required IL-1β-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-1β-mediated cell death. Importantly, SMC-resistant cells that produced TNFα in response to IL-1β 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-1β 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkynes / agonists
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Alkynes / pharmacology*
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Animals
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Antineoplastic Agents / agonists
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Baculoviral IAP Repeat-Containing 3 Protein
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CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
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CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
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Caspase 8 / genetics
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Caspase 8 / metabolism
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Cell Line, Tumor
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Dipeptides / agonists
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Dipeptides / pharmacology*
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Drug Screening Assays, Antitumor
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Drug Synergism
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Gene Knockdown Techniques
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Humans
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism
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Interleukin-1beta / agonists
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Interleukin-1beta / pharmacology*
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Mice
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Neoplasms / drug therapy*
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Neoplasms / genetics
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Neoplasms / metabolism
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Peptidomimetics / agonists
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Peptidomimetics / pharmacology*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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Ubiquitin-Protein Ligases
Substances
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AEG 40730
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Alkynes
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Antineoplastic Agents
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Cflar protein, mouse
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Dipeptides
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Inhibitor of Apoptosis Proteins
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Interleukin-1beta
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NF-kappa B
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Peptidomimetics
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Tumor Necrosis Factor-alpha
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BIRC3 protein, human
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Baculoviral IAP Repeat-Containing 3 Protein
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Ubiquitin-Protein Ligases
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CASP8 protein, human
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Casp8 protein, mouse
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Caspase 8