Smac mimetic compounds potentiate interleukin-1beta-mediated cell death

J Biol Chem. 2010 Dec 24;285(52):40612-23. doi: 10.1074/jbc.M110.183616. Epub 2010 Oct 18.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes / agonists
  • Alkynes / pharmacology*
  • Animals
  • Antineoplastic Agents / agonists
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Baculoviral IAP Repeat-Containing 3 Protein
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Caspase 8 / genetics
  • Caspase 8 / metabolism
  • Cell Line, Tumor
  • Dipeptides / agonists
  • Dipeptides / pharmacology*
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Gene Knockdown Techniques
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors
  • Inhibitor of Apoptosis Proteins / genetics
  • Inhibitor of Apoptosis Proteins / metabolism
  • Interleukin-1beta / agonists
  • Interleukin-1beta / pharmacology*
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Peptidomimetics / agonists
  • Peptidomimetics / pharmacology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Ubiquitin-Protein Ligases

Substances

  • AEG 40730
  • Alkynes
  • Antineoplastic Agents
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cflar protein, mouse
  • Dipeptides
  • Inhibitor of Apoptosis Proteins
  • Interleukin-1beta
  • NF-kappa B
  • Peptidomimetics
  • Tumor Necrosis Factor-alpha
  • BIRC3 protein, human
  • Baculoviral IAP Repeat-Containing 3 Protein
  • Ubiquitin-Protein Ligases
  • CASP8 protein, human
  • Casp8 protein, mouse
  • Caspase 8