Growth Horm IGF Res. 2015 Jul 20. pii: S1096-6374(15)30019-8. doi: 10.1016/j.ghir.2015.07.008. [Epub ahead of print]

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

Li S1, Pinard M2, Wang Y2, Yang L1, Lin R3, Hiscott J4, Su B5, Brodt P6.

Author information

• 1Dept of Medicine, McGill University and the McGill University Health Center, Canada.
• 2Dept of Surgery, McGill University and the McGill University Health Center, Canada.
• 3Dept of Medicine, McGill University and the McGill University Health Center, Canada; The Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Montreal QC, Canada.
• 4Dept of Medicine, McGill University and the McGill University Health Center, Canada; Dept of Microbiology and Immunology, McGill University, Canada; The Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Montreal QC, Canada.
• 5Dept of Immunobiology, Yale School of Medicine, New Haven, CT, United States.
• 6Dept of Medicine, McGill University and the McGill University Health Center, Canada; Dept of Surgery, McGill University and the McGill University Health Center, Canada. Electronic address: pnina.brodt@mcgill.ca.

Abstract

BACKGROUND:

The receptor for type I insulin like growth factor (IGF-IR) and NFκB 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 -α (ΤΝF-α)-induced apoptosis by activating autocrine, pro-survival IL-6/gp130/STAT3 signaling, suggesting that IGF-IR expression could alter NF-κB signaling that is required for transcriptional activation of IL-6.

OBJECTIVE:

Here we sought to determine if and how IGF-IR signaling promotes TNF-α-induced NFκB activation.

DESIGN:

We used lung carcinoma M-27 and colon carcinoma MC-38 cells to investigate IGF-IR-induced changes to the IKK/IκBα/NFκB 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 NFκB in response to TNF-α was enhanced in lung and colon carcinoma cells and this was due to accelerated phosphorylation and degradation of IκBα. This effect was AKT-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-κB signaling in cancer cells in an AKT/MEKK3-dependent manner and that temporal aspects of NF-κB activation can regulate the cytokine profile of the tumor cells and thereby, their interaction with the microenvironment.