Cellular inhibitor of apoptosis-1 (cIAP1) is a signaling regulator with oncogenic properties. It is involved in the regulation of signaling pathways controlling inflammation, cell survival, proliferation, differentiation and motility. It is recruited into membrane-receptor-associated signaling complexes thanks to the molecular adaptor TRAF2. However, the cIAP1/TRAF2 complex exists, independently of receptor engagement, in several subcellular compartments. The present work strengthens the importance of TRAF2 in the oncogenic properties of cIAP1. cIAPs-deficient mouse embryonic fibroblasts (MEFs) were transformed using the HRas-V12 oncogene. Re-expression of cIAP1 enhanced tumor growth in a nude mice xenograft model, and promoted lung tumor nodes formation. Deletion or mutation of the TRAF2-binding site completely abolished the oncogenic properties of cIAP1. Further, cIAP1 mediated the clustering of TRAF2, which was sufficient to stimulate tumor growth. Our TRAF2 interactome analysis showed that cIAP1 was critical for TRAF2 to bind to its protein partners. Thus, cIAP1 and TRAF2 would be two essential subunits of a signaling complex promoting a pro-tumoral signal. cIAP1/TRAF2 promoted the activation of the canonical NF-κB and ERK1/2 signaling pathways. NF-κB-dependent production of IL-6 triggered the activation of the JAK/STAT3 axis in an autocrine manner. Inhibition or downregulation of STAT3 specifically compromised the growth of cIAP1-restored MEFs but not that of MEFs expressing a cIAP1-mutant and treating mice with the STAT3 inhibitor niclosamide completely abrogated cIAP1/TRAF2-mediated tumor growth. Altogether, we demonstrate that cIAP1/TRAF2 binding is essential to promote tumor growth via the activation of the JAK/STAT3 signaling pathway.
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We thank Pauline Maes from the CLIPP proteomic platform, University of Burgundy, Philippe Hammann from the Strasbourg proteomic platform, IBMC, Valérie Saint-Gorgio from zootechny center, University of Burgundy, and Romain Aucagne from the Crigen platform, University of Burgundy. This work was supported by grants from the ‘Comités de Côte d’Or et de l’Yonne’ of the ‘Ligue Contre le Cancer’ (LD), La Ligue Nationale contre le Cancer (CG’s team), the European Union and the ‘Conseil Régional de Bourgogne’, a French Government grant managed by the French National Research Agency under the program ‘Investissements d’Avenir’ with reference ANR-11-LABX-0021, and fellowships from the ‘Ministère de l’Enseignement Supérieur et de la Recherche’ of France (to BD, AZ, JB and JA), the ‘Fondation ARC pour la Recherche sur le Cancer’ (to BD). We thank the FEDER for their financial support.
The authors declare no competing interests.
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Dumétier, B., Zadoroznyj, A., Berthelet, J. et al. cIAP1/TRAF2 interplay promotes tumor growth through the activation of STAT3. Oncogene 42, 198–208 (2023). https://doi.org/10.1038/s41388-022-02544-y