No abstract

Intrarenal interleukin-15 (IL-15) plays a major role controlling epithelial survival and polarization both in physiological and pathologic conditions. Herein, we confirmed that human renal cell carcinomas (RCCs) express a membrane-bound IL-15 isoform displaying an unusual molecular weight of 27 kDa. Its stimulation with soluble IL-15 receptor α chain (s-IL-15Rα) triggers epithelial-mesenchymal transition (EMT) process as shown by the down-regulation of E-cadherin and zona occludens 1 and the up-regulation of vimentin and N-cadherin and promotes the migratory and invasive properties of RCC. S-IL-15Rα treatment triggered the Src/PI3K/Akt/GSK-3β pathway and promoted β-catenin nuclei translocation. Deactivation of this pathway by using Src-specific inhibitor PP2, PI3K inhibitor LY294002, and AKT inhibitor MK2206 hampered β-catenin nuclei translocation and suppressed EMT, migration, and invasion of RCC. S-IL-15Rα treatment also enhanced Src-dependent phosphorylation of focal adhesion kinase (FAK) and extracellular signal–regulated kinase (Erk1/2). FAK knockdown significantly decreased the migration and invasion of RCC, which suggest that Src-FAK signaling was involved in s-IL-15Rα–favored migration and invasion of RCC. At the same time, inhibitors of Erk1/2 also significantly decreased the migration and invasion of RCC but could not reverse s-IL-15Rα–induced EMT. Taken together, our results reveal that Src-dependent PI3K/Akt/GSK3b/β-catenin pathway is required for s-IL-15Ra–dependent induction of EMT in RCC, while Src-FAK and Src-Erk1/2 signaling were involved in s-IL-15Rα–promoted migration and invasion properties of RCC. Our study provides a better understanding of IL-15 signaling in RCC tumor progression, which may lead to novel targeted therapies and provide some suggestions when using IL-15 in clinic.

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In this study, we investigated the antitumor activity of axitinib, a selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases, against melanoma cells. Axitinib dose-dependently inhibited the proliferation and induced the apoptosis of B16F1 cells in vitro. In a mouse model of melanoma xenograft, axitinib significantly suppressed tumor growth and induced apoptosis of cells in tumor tissues at a dose of 25 mg/kg. In addition, axitinib suppressed the lung metastasis of melanoma cells and prolonged the life span of tumor-bearing mice. Axitinib also enhanced the proportion of CD8⁺ T cells and reduced the proportion of myeloid-derived suppressor cells in CD45.2⁺ cells, whereas the proportions of CD4⁺ T cells and Treg cells were not affected. The mRNA expressions of inducible nitric oxide synthases-2 and arginase-1, which were associated with the function of myeloid-derived suppressor cells in tumor tissues, were inhibited by axitinib. Moreover, axitinib suppressed the expressions of proinflammatory cytokines such as IL-6, TNF-α, and IFN-γ. Altogether, our results showed the unique antitumor mechanism of axitinib and provided useful information for its clinical application.