Crosstalk between the TNF and IGF pathways enhances NF-κB activation and signaling in cancer cells

Background: The receptor for type! insulin like growth factor (IGF-IR) and NF kappa B signaling both play essential roles in cancer initiation and progression but relatively little is known about possible crosstalk between these pathways. We have shown that the IGF-IR could rescue lung and colon carcinoma cells from Tumor necrosis factor -alpha (TNF-alpha)-induced apoptosis by activating autocrine, pro-survival IL-6/gp130/STAT3 signaling, suggesting that IGF-IR expression could alter NF-kappa B signaling that is required for transcriptional activation of IL-6. Objective: Here we sought to determine if and how IGF-IR signaling promotes TNF-alpha-induced NF kappa B activation. Design: We used lung carcinoma M-27 and colon carcinoma MC-38 cells to investigate IGF-IR-induced changes to the IKK/I kappa B alpha/NF kappa B pathway by a combination of qPCR, Western blotting, electrophoretic mobility shift assay, a reporter assay and gene silencing. Results: We show that in the presence of increased IGF-IR expression or activation levels, nuclear translocation of NF kappa B in response to TNF-alpha was enhanced in lung and colon carcinoma cells and this was due to accelerated phosphorylation and degradation of I kappa B alpha. This effect was Ala-dependent and mediated via mitogen-activated protein kinase kinase kinase 3 (MEKK3) activation. Conclusion: The results suggest that ligand-mediated activation of IGF-IR alters NF-kappa B signaling in cancer cells in an AKT/MEKK3-dependent manner and that temporal aspects of NF-kappa B activation can regulate the cytokine profile of the tumor cells and thereby, their interaction with the microenvironment. (C) 2015 Elsevier Ltd. All rights reserved.