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cIAP1/TRAF2 interplay promotes tumor growth through the activation of STAT3

Oncogene volume 42, pages 198–208 (2023)Cite this article

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Abstract

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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Fig. 1: TRAF2 binding is critical for the oncogenic activity of cIAP1.
Fig. 2: Forced clustering of TRAF2 stimulated tumor growth, independently of cIAP1.
Fig. 3: TRAF2 interactome.
Fig. 4: TRAF2 binding is essential for the activation of the canonical NF-κB and ERK1/2 signaling pathways.
Fig. 5: cIAP1 and TRAF2 are critical for the activation of the JAK/STAT3 signaling pathways.
Fig. 6: STAT3 signaling pathway is required for cIAP1-mediated tumor cell growth.

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Figshare https://doi.org/10.6084/m9.figshare.21399906.

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Acknowledgements

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.

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Author notes

  1. Jean Berthelet

    Present address: Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia

  2. These authors contributed equally: Baptiste Dumétier, Aymeric Zadoroznyj.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (Inserm), LNC UMR1231, LabEx LIpSTIC, Team with the label of excellence from «la ligue national contre le Cancer», 21000, Dijon, France

    Baptiste Dumétier, Aymeric Zadoroznyj, Jean Berthelet, Sébastien Causse, Jennifer Allègre, Pauline Bourgeois, Florine Cattin, Carmen Garrido & Laurence Dubrez

  2. Université de Bourgogne-Franche-Comté, 21000, Dijon, France

    Baptiste Dumétier, Aymeric Zadoroznyj, Jean Berthelet, Sébastien Causse, Jennifer Allègre, Pauline Bourgeois, Florine Cattin, Carmen Garrido & Laurence Dubrez

  3. LIIC, EA7269, Université de Bourgogne-Franche-Comté, 21000, Paris, France

    Cindy Racoeur & Catherine Paul

  4. Laboratory of Immunology and Immunotherapy of Cancers, EPHE, PSL Research University, 75000, Paris, France

    Cindy Racoeur & Catherine Paul

  5. Anticancer Center Georges François Leclerc-Unicancer, Dijon, France

    Carmen Garrido

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Contributions

BD and AZ performed most of the experiments and analyzed the data. JB initiated the project, established the tumor model, and performed some in vivo experiments. SC performed immunofluorescence analysis. JA, PB, and FC helped in performing western blots, clonogenicity assays, and in vivo experiments. CR and CP brought expertise in in vivo model and performed IV injection. CG provided scientific expertise and corrected the paper and LD conceived and supervised the project, conducted the GEPIA analysis, analyzed the data and interpreted the results, wrote the paper with input from all authors.

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Correspondence to Laurence Dubrez.

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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

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