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

Herman H Cheung,Shawn T Beug,Martine St Jean,Audrey Brewster,N Lynn Kelly,Shaomeng Wang,Robert G Korneluk

doi:10.1074/jbc.m110.183616

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.

Highlights

Motherapeutics [1,2,3]
We demonstrate that IL-1␤ treatment induces NF-␬B-dependent production of TNF␣, which triggers receptor interacting protein 1 (RIP1)- and caspase 8-dependent apoptosis when the inhibitor of apoptosis (IAP) are down-regulated by SMC treatment
In those cancer cells that are resistant to SMC and IL-1␤ treatment, cellular resistance can be overcome by the down-regulation of the caspase-8 inhibitor c-FLIP

Summary

Introduction

Motherapeutics [1,2,3]. Cytokines and chemokines are the principal mediators of pro-inflammatory responses that shape the progression of malignancy. In addition to sensitizing cells to TNF␣-mediated apoptosis, down-regulation of the cIAPs promotes cell death in response to TNF-related apoptosis-inducing ligand (TRAIL), DR5/ TRAILR2 agonist antibody, and FasL treatment. Similar to caspase-8 silencing, down-regulation of RIP1 protected these cells against SMC-mediated IL-1␤-induced cell death (Fig. 3, A–C, lane 9).

Results

Conclusion