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Article Dans Une Revue Oncogene Année : 2022

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

Baptiste Dumétier
  • Fonction : Auteur
Aymeric Zadoroznyj
  • Fonction : Auteur
Jean Berthelet
  • Fonction : Auteur
Sébastien Causse
  • Fonction : Auteur
Jennifer Allègre
  • Fonction : Auteur
Pauline Bourgeois
  • Fonction : Auteur
Florine Cattin
  • Fonction : Auteur
Cindy Racoeur
  • Fonction : Auteur
Catherine Paul
  • Fonction : Auteur
Carmen Garrido
  • Fonction : Auteur

Résumé

Cellular inhibitor of apoptosis-1 (cIAP1) is a signaling regulator with oncogenic properties. It is involved in the regulation ofsignaling pathways controlling inflammation, cell survival, proliferation, differentiation and motility. It is recruited into membranereceptor-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 ofTRAF2 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 nodesformation. Deletion or mutation of the TRAF2-binding site completely abolished the oncogenic properties of cIAP1. Further, cIAP1mediated the clustering of TRAF2, which was sufficient to stimulate tumor growth. Our TRAF2 interactome analysis showed thatcIAP1 was critical for TRAF2 to bind to its protein partners. Thus, cIAP1 and TRAF2 would be two essential subunits of a signalingcomplex promoting a pro-tumoral signal. cIAP1/TRAF2 promoted the activation of the canonical NF-κB and ERK1/2 signalingpathways. NF-κB-dependent production of IL-6 triggered the activation of the JAK/STAT3 axis in an autocrine manner. Inhibition ordownregulation 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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Dates et versions

hal-03882909 , version 1 (02-12-2022)

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Baptiste Dumétier, Aymeric Zadoroznyj, Jean Berthelet, Sébastien Causse, Jennifer Allègre, et al.. cIAP1/TRAF2 interplay promotes tumor growth through the activation of STAT3. Oncogene, In press, ⟨10.1038/s41388-022-02544-y⟩. ⟨hal-03882909⟩
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