Inhibition by platelet-activating factor of Src- and hepatocyte growth factor-dependent invasiveness of intestinal and kidney epithelial cells. Phosphatidylinositol 3'-kinase is a critical mediator of tumor invasion
| Autor: | L, Kotelevets, V, Noë, E, Bruyneel, E, Myssiakine, E, Chastre, M, Mareel, C, Gespach |
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| Rok vydání: | 1998 |
| Předmět: |
Morpholines
Receptors Cell Surface Platelet Membrane Glycoproteins Kidney Receptors G-Protein-Coupled Dogs Transformation Genetic Cell Movement GTP-Binding Proteins Tumor Cells Cultured Animals Humans Virulence Factors Bordetella Intestinal Mucosa Phosphorylation Platelet Activating Factor Phosphoinositide-3 Kinase Inhibitors Hepatocyte Growth Factor Azepines Protein-Tyrosine Kinases Triazoles Androstadienes Gene Expression Regulation Neoplastic Genes src Thiazoles Pertussis Toxin Chromones Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases Colonic Neoplasms Wortmannin Cell Adhesion Molecules Platelet Aggregation Inhibitors Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 273(23) |
| ISSN: | 0021-9258 |
| Popis: | This study was designed to characterize platelet-activating factor receptor (PAF-R) expression and function in normal and cancerous human colonic epithelial cells. PAF-R gene transcripts were analyzed by reverse transcription-polymerase chain reaction and Southern blot, using three sets of primers corresponding either to the coding region of the human PAF-R sequence (polymerase chain reaction product: 682 base pairs (bp)) or to the leukocyte- and tissue-type transcripts of 166 and 252 bp, respectively. An elongated splice variant was identified in the 5'-untranslated region of the tissue-type PAF-R transcript (334 bp) in colonic epithelial crypts and tumors. In human colonic PCmsrc cells transformed by c-src oncogene, the hepatocyte growth factor (HGF)-dependent invasiveness of collagen gels was abolished by 0.1 microM PAF and restored by the PAF-R antagonists WEB2086 and SR27417. PAF blocked HGF-induced tyrosine phosphorylation of p125 focal adhesion kinase. The phosphatidylinositol 3'-kinase (PI3'-K) inhibitors wortmannin and LY294002 totally blocked the HGF-induced invasion. Similar effects were observed in ts-srcMDCK kidney epithelial cells transformed by a v-Src temperature-sensitive mutant: (i) PAF and wortmannin exerted additive inhibitory effects on Src-induced invasion and (ii) activated and dominant negative forms of p110alpha PI3'-K, respectively, amplified and abrogated the Src- and HGF-dependent invasiveness of parental and ts-srcMDCK cells. We also provided the first evidence for the contribution of rapamycin-insensitive, pertussis toxin-dependent G-protein pathways to the integration of the signals emerging from activated Met and PAF receptors. These results indicate that PI3'-K is a critical transducer of invasiveness and strongly suggest that PAF exerts a negative control on invasion by inhibiting this signaling pathway. A possible beneficial role of PAF analogs on tumor invasion is therefore proposed. |
| Databáze: | OpenAIRE |
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