Poster Presentation 25th Lorne Cancer Conference 2013

IAPs limit RIPK1-induced TNF biosynthesis (#240)

Najoua Lalaoui 1 , Diep Chau 1 , Lynn W Wong 2 , John Silke 1
  1. Walter and Eliza Hall Institute of Medical Research, Parville, VIC, Australia
  2. Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

Smac-mimetic compounds are currently in cancer Phase I clinical trials. We have shown Smac-mimetics antagonize Inhibitor APoptosis proteins (IAPs) and induce TNF production leading to the death of a subset of cancerous and as well as primary cells. High concentrations of TNF are toxic therefore it is essential to understand how Smac-mimetics drive TNF production. We have shown that Receptor-interacting protein kinase 1 (RIPK1) and RIPK3 induce directly TNF production when IAPs are depleted. Interestingly, we show that in addition to NF-κB signaling, the MAPK pathway is also involved in the regulation of TNF synthesis following IAPs inhibition. Our results suggest that IAPs limit spontaneous TNF expression by regulating RIPK1-mediated NF-κB and MAPK activities.