Aymeric Zadoroznyj, Baptiste Dumétier, Laurence Dubrez INSERM u-1231, UFR des Sciences de Santé, Dijon, France
With approximately 10 million deaths per year, cancer is the second most lethal disease in the world. To overcome this major public health issue, new targets for therapies are needed. One of them, cIAP1 (cellular Inhibitor of APoptosis-1) is a E3 ubiquitin ligase protein with oncogenic properties. cIAP1 expression is frequently altered in various human tumor samples and represents a predictive marker of poor prognosis and chemoresistance. Several IAP antagonists (Smac mi- metics) have been synthesized. They show promising results in preclinical studies and some of them are currently being tested in clinical studies. These molecules are poorly specific as they can neutralize several IAP family members.
cIAP1 is involved in various cellular processes such as proliferation, differentiation, cell cycle regulation, inflammation, and cell migration that can account for its oncogenic properties. We established a tumor model confirming the oncogenic properties of cIAP1. Mouse embryonic fibroblasts (MEF) lacking cIAP1 and cIAP2 were transformed by HRas-V12 oncogene. Restoration of cIAP1 considerably increases tumor growth and lung foci formation in animals. Expressing cIAP1 mutants unable to bind TRAF2 (ΔBIR1 or L47A mutants) completely abolished the capacity of cIAP1 to stimulate tumor growth. The expression of isolated cIAP1-BIR1 domain that induces clustering of TRAF2 is sufficient to stimulate tumor growth. The analysis of TRAF2 interactome by mass spectrometry reveals that cIAP1 is critical for binding TRAF2 to its interactome. Indeed, cIAP1 deletion by the SMAC mimetic GDC-0152 greatly reduces the number of TRAF2 partners.cIAP1- TRAF2 promotes the activation of canonical-NF-τB and ERK1/2 signaling pathways and stimulates the phosphorylation of STAT3 and JAK2, two effector proteins involved in different pathways as the IL6R or EGF-R pathways. The capacity of cIAP1 and TRAF2 to control STAT3-dependant signalling pathways has been confirmed in the human A549 lung cancer by siRNA strategies. The present work identified a novel function for cIAP1 that appears essential to TRAF2 to bind its protein partners. Conversely, TRAF2 is required for oncogenic properties of cIAP1. cIAP1-TRAF2 induced the activation of canonical NF-τB, ERK1/2. Moreover, we demonstrated the capacity of cIAP1 – TRAF2 to stimulate jak2/STAT3 signalling pathway that appears important in oncogenic properties of cIAP1.