Background: Degradation of insulin-like growth factor 1 receptor (IGF-1R) is mediated by internalization and endocytosis, for which ubiquitin-proteasome pathways play as a regulatory system. Cezanne expression is positively associated with IGF-1R expression. High Cezanne expression correlates with poor patient survival in NSCLC, yet the underlying mechanisms are not well defined. Methods: Co-Immunoprecipitation assay was performed to investigate the interactions between Cezanne and IGF-1R. A xenograft model was established to assess the efficacy of Cezanne on cancer progression in vivo. Cezanne overexpressing and Cezanne knockdown NSCLC cell lines were generated using lentiviral vectors. The effects of Cezanne and IGF-1R on cell proliferation of non-small-cell lung cancer were evaluated via Sulforhodamine B assay and colony formation assays. Results: Here, through co-Immunoprecipitation assay, we find Cezanne interacts with IGF-1R in tumor cells. Depletion of Cezanne promotes the ubiquitination and degradation of IGF-1R. Congruently, Cezanne regulates the protein level of IGF-1R and downstream AKT signaling pathway. Cezanne promotes proliferation of tumor cells in vitro and in vivo. In line with the change of IGF-1R downstream signaling pathway, IGF-1-induced growth signals recover cell proliferation of tumor cells with Cezanne knockdown. Conclusion: Mechanistically, Cezanne directly targets IGF-1R by deubiquitination and stabilization. This leads to AKT activation, which bolsters tumor cell growth in vitro and in vivo. These findings reveal Cezanne as a regulator of tumor cell proliferation via IGF-1R signaling pathway and a potential target for NSCLC therapy.
Keywords: Cezanne; IGF-1R; NSCLC; deubiquitination.
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