title: Crosstalk between the TNF and IGF pathways enhances NF-κB activation and signaling in cancer cells.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Dept of Medicine, McGill University and the McGill University Health Center, Canada.
authors.forename: Shun
authors.initials: S
authors.lastname: Li
authors.affiliation: Dept of Surgery, McGill University and the McGill University Health Center, Canada.
authors.forename: Maxime
authors.initials: M
authors.lastname: Pinard
authors.affiliation: Dept of Surgery, McGill University and the McGill University Health Center, Canada.
authors.forename: Yunling
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Dept of Medicine, McGill University and the McGill University Health Center, Canada.
authors.forename: Long
authors.initials: L
authors.lastname: Yang
authors.affiliation: Dept 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.
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.affiliation: Dept 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.
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
authors.affiliation: Dept of Immunobiology, Yale School of Medicine, New Haven, CT, United States.
authors.forename: Bing
authors.initials: B
authors.lastname: Su
authors.affiliation: Dept 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.
authors.forename: Pnina
authors.initials: P
authors.lastname: Brodt
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D048748:MAP Kinase Kinase Kinase 3 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020239:Receptor Cross-Talk; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction; D013002:Somatomedins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D013002:Somatomedins; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D048748:MAP Kinase Kinase Kinase 3; C482626:Map3k3 protein, mouse
keywords: IGF; MEKK3; NF-κB; Signaling; TNF