midostaurin and Carcinoma

The intracellular signaling involved in the mechanism of action of zonula occludens toxin (ZOT) was studied using several in vitro and ex vivo models. ZOT showed a selective effect among various cell lines tested, suggesting that it may interact with a specific receptor, whose surface expression on various cells differs. When tested in IEC6 cell monolayers, ZOT-containing supernatants induced a redistribution of the F-actin cytoskeleton. Similar results were obtained with rabbit ileal mucosa, where the reorganization of F-actin paralleled the increase in tissue permeability. In endothelial cells, the cytoskeletal rearrangement involved a decrease of the soluble G-actin pool (-27%) and a reciprocal increase in the filamentous F-actin pool (+22%). This actin polymerization was time- and dose-dependent, and was reversible. Pretreatment with a specific protein kinase C inhibitor, CGP41251, completely abolished the ZOT effects on both tissue permeability and actin polymerization. In IEC6 cells ZOT induced a peak increment of the PKC-alpha isoform after 3 min incubation. Taken together, these results suggest that ZOT activates a complex intracellular cascade of events that regulate tight junction permeability, probably mimicking the effect of physiologic modulator(s) of epithelial barrier function.

Topics: Actins; Adenosine Triphosphatases; Alkaloids; Animals; Carcinoma; Cattle; Cell Line; Cholera Toxin; Colonic Neoplasms; Cytoskeleton; Endothelium, Vascular; Endotoxins; Humans; Ileum; Intercellular Junctions; Intestinal Mucosa; Isoenzymes; Kidney Cortex; Male; Organ Specificity; Permeability; Phosphatidylinositol Diacylglycerol-Lyase; Phosphoric Diester Hydrolases; Protein Kinase C; Pulmonary Artery; Rabbits; Rats; Signal Transduction; Species Specificity; Staurosporine; Swine; Tumor Cells, Cultured; Vibrio cholerae