title: Butyrate-treated colonic Caco-2 cells exhibit defective integrin-mediated signaling together with increased apoptosis and differentiation.
abstract: We previously reported that the enterocytic differentiation of human colonic Caco-2 cells correlated with alterations in integrin signaling. We now investigated whether differentiation and apoptosis of Caco-2 cells induced by the short-chain fatty acid butyrate (NaBT) was associated with alterations in the integrin-mediated signaling pathway with special interest in the expression and activity of focal adhesion kinase (FAK), of the downstream phosphatidylinositol 3'-kinase (PI 3-kinase)-Akt pathway and in the role of the nuclear factor kappaB (NF-kappaB). NaBT increased the level of sucrase. It induced apoptosis as shown by: (1) decreased Bcl-2 and Bcl-X(L) proteins and increased Bax protein; (2) activation of caspase-3; and (3) increased shedding of apoptotic cells in the medium. This effect was associated with defective integrin-mediated signaling as shown by: (1) down-regulation of beta1 integrin expression; 2) decreased FAK expression and tyrosine phosphorylation; (3) concerted alterations in cytoskeletal and structural focal adhesions proteins (talin, ezrin); and (4) decreased FAK ability to associate with PI 3-kinase. However, in Caco-2 cells, beta1-mediated signaling failed to be activated downstream of FAK and PI 3-kinase at the level of Akt. Transfection studies show that NaBT treatment of Caco-2 cells promoted a significant activation of the NF-kappaB which was probably involved in the NaBT-induced apoptosis. Our results indicate that the prodifferentiating agent NaBT induced apoptosis of Caco-2 cells probably through NF-kappaB activation together with a defective beta1 integrin-FAK-PI 3-kinase pathways signaling.
authors.affiliation: INSERM U. 402, Faculté de Médecine Saint-Antoine, rue Chaligny, Paris Cedex, France. levy@st-antoine.inserm.fr
authors.forename: Peggy
authors.initials: P
authors.lastname: Lévy
authors.forename: Hélène
authors.initials: H
authors.lastname: Robin
authors.forename: France
authors.initials: F
authors.lastname: Bertrand
authors.forename: Michel
authors.initials: M
authors.lastname: Kornprobst
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Capeau
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002087:Butyrates / Q000494:pharmacology; D018938:Caco-2 Cells; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D019012:Integrin beta1 / Q000187:drug effects / Q000378:metabolism; D016023:Integrins / Q000187:drug effects / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013393:Sucrase / Q000187:drug effects / Q000378:metabolism
chemical_list: D002087:Butyrates; D053148:Caspase 3; D020169:Caspases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019012:Integrin beta1; D016023:Integrins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D013393:Sucrase; C496050:PTK2 protein, human; C494918:AKT1 protein, human; C505407:CASP3 protein, human