Oral Presentation 26th Lorne Cancer Conference 2014

IAPs and RIPKs modulate sensitivity to TNF induced apoptosis and cancer formation (#5)

W. Wei-Lynn (Lynn) Wong 1 , Najoua Lalaoui 2 , Kate Lawlor 2 , Kay Haenggi 1 , Diep Chau 2 , Aleksandra Bankovacki 2 , Holly Anderton 2 , Anissa Jabbour 2 , Lorraine O'Reilly 2 , Don Metcalf 2 , Paul Ekert 2 , James E Vince 2 , Andreas Strasser 2 , David Vaux 2 , John Silke 2
  1. University of Zurich, Zürich, Switzerland
  2. Walter + Eliza Hall Institute of Medical Research, Melbourne

Inhibitors of apoptosis proteins were initially found due to their ability to block apoptosis.  In certain tumor types, loss of cIAP1 by pharmacological inhibitors called Smac-mimetics cause an autocrine TNF/TNFR1-mediated cell death.  However, cIAP1 knock-out mice are healthy and fertile suggesting that either the loss of cIAP1 to produce cytokine production requires additional transforming events or the additional loss of cIAP2 or XIAP is required for the production of TNF.  We show that the addition of particular oncogenes such as MYC but not Ras in a primary cIAP1 knockout cell the signal from TNF from survival to cell death.  These results suggest tumors with particular mutations should be targetted for Smac-mimetic treatment.  In addition, we found that in primary cell types, such as monocyte/macrophages, the loss of XIAP and cIAP1/2 is required to cause the production of TNF.  When RIPK1 or RIPK3 was inhibited or genetically deleted, we found that cell death was blocked or attenuated but surprisingly, not due to inhibition of necrosis but due to the loss or reduced TNF production.  This suggests that in certain cell types, one of the main physiological role of IAPs and RIPKs are to modulate cytokine production. This role is separable from the role of RIPK in programmed necrosis.  We hypothesis IAPs and RIPKs modulate the tumor microenvironment to aid in cancer formation and have established tumor models in which to examine the effect of these proteins in cancer formation.