title: Prevention of cytokine-induced apoptosis by insulin-like growth factor-I is independent of cell adhesion molecules in HT29-D4 colon carcinoma cells-evidence for a NF-kappaB-dependent survival mechanism.
abstract: We have previously established that insulin-like growth factor (IGF)-I, -II and insulin exert a strong protective effect against tumor necrosis factor-alpha (TNF)-induced apoptosis in interferon-gamma (IFN)-sensitized HT29-D4 human colon carcinoma cells. In this study, we report that this effect was still operative when cells were cultured in the absence of integrin- and E-cadherin-mediated cell-extracellular matrix and cell-cell interactions. In this model, IGF-I did not activate the focal adhesion kinase, whereas it induced tyrosine phosphorylation of the insulin receptor substrate-1 and activation of the extracellular signal-related kinase 1 and 2, p38, phosphatidylinositol 3'-kinase and protein kinase B/Akt. However, the use of specific inhibitors indicated that these pathways did not play a role in the adhesion-independent IGF-I anti-apoptotic signal. In contrast, inhibition of the NF-kappaB activation induced a complete reversal of the IGF-I anchorage-independent protective effect. Correspondingly, IGF-I markedly enhanced the TNF- and IFN/TNF-induced NF-kappaB-dependent interleukin-8 production. Our results provide evidence that IGF-I induces resistance against cytokine-induced cell death even in the absence of cell adhesion-mediated signaling. NF-kappaB appears to be a key mediator of this anti-apoptotic effect that should contribute to the resistance of colon cancer cells to immune-destruction during metastasis.
authors.affiliation: UMR CNRS 6032, Facultés de Médecine et de Pharmacie, Université de la Méditerranée, Marseille, France.
authors.forename: F
authors.initials: F
authors.lastname: Garrouste
authors.forename: M
authors.initials: M
authors.lastname: Remacle-Bonnet
authors.forename: C
authors.initials: C
authors.lastname: Fauriat
authors.forename: J
authors.initials: J
authors.lastname: Marvaldi
authors.forename: J
authors.initials: J
authors.lastname: Luis
authors.forename: G
authors.initials: G
authors.lastname: Pommier
mesh_terms: D017209:Apoptosis; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002450:Cell Communication; D002470:Cell Survival; D004351:Drug Resistance; D005109:Extracellular Matrix / Q000378:metabolism; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019073:HT29 Cells; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D015815:Cell Adhesion Molecules; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D007371:Interferon-gamma; D016209:Interleukin-8; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C526292:IRS1 protein, human; C496050:PTK2 protein, human; C494918:AKT1 protein, human