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Glycine-extended gastrin activates two independent tyrosine-kinases in upstream of p85/p110 phosphatidylinositol 3-kinase in human colonic tumour cells

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World Journal of Gastroenterology 2006年第12期12卷 1859-1864页

作者： Audrey Ferrand Aline Kowalski-Chauvel Claudine Bertrand Daniel Fourmy Marlene Dufresne catherine seva Julie Pannequin INSERM U.531 Groupe de Recherche de Biologie et Pathologie DigestivesIFR31Institut Louis BugnardBP 8422531432 toulouse Cedex 4France University of Melbourne Department of Surgery Austin CampusARMCHeidelbergVictoria 3084Australia

AIM： To investigate whether Src, JAK2 and phosphatidylinositol 3-kinase （PI3K） pathways are involved in the proliferation of human colonic tumour cells induced by glycine-extended gastrin （G-gly）, the precursor of the mature amidated gastrin and to elucidate the molecular interaction between these three kinases in response to this peptide. METHODS： Using the human colonic tumour cell line HCT116 as a model, we first measured the activation of PI3K, p60-Src and JAK2 in response to G-gly by in vitro kinase assays. Then we investigated the involvement of these kinases in G-gly-induced cell proliferation by MTT test. RESULTS： G-gly stimulation induced p60-Src, JAK2 and PI3K activation in HCT116. The different pathways were involved in proliferation of human colon cancer cells induced by G-gly. Furthermore, we found that both Src and JAK2 were necessary to PI3K regulation by this peptide. However, we did not find any cross-talk between the two tyrosine kinases. CONCLUSION： Our results suggest that the p60-Src/ PI3K and JAK2/PI3K pathways act independently to mediate G-gly proliferative effect on human colonic tumour cells.

关键词： Colon cancer Src JAK2 Phosphatidylinositol 3-kinase Glycine-extended gastrin

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Mechanism for Src activation by the CCK2 receptor:Patho-physiological functions of this receptor in pancreas

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World Journal of Gastroenterology 2006年第28期12卷 4498-4503页

作者： Audrey Ferrand Sebastien Vatinel Aline Kowalski-Chauvel Claudine Bertrand Chantal Escrieut Daniel Fourmy Marlene Dufresne catherine seva Dufresne Catherine SevaINSERM U 531IFR 31Institut Louis BugnardBP 8422531432 Toulouse cedex 4France

AIM： TO investigate in vivo, whether CCK2 receptors （CCK2R） regulate proteins known to play a crucial role in cell proliferation and cancer development and analyse in vitro the molecular mechanisms that lead to Src activation; in particular, to identify the domains within the CCK2R sequence that are implicated in this activation. METHODS： The expression and activation of Src and ERK were studied in vivo using immunofluorescence and western-blot techniques. We used pancreatic tissues derived from wild type or Elas-CCK2 mice that expressed the CCK2R in pancreatic acini, displayed an increased pancreatic growth and developed preneoplastic lesions. The pancreatic tumor cell line AR4-2J expressing the endogenous CCK2R or COS-7 cells transiently transfected with wild type or mutant CCK2R were used as in vitro models to study the mechanism of Src activation. Src activation was measured by in vitro kinase assays, ERK activation by western blot using antiphospho-ERK antibodies and the involvement of Src in gastrin-induced cell proliferation by MTT test. RESULTS： We showed in vivo that the targeted CCK2R expression in the pancreas of Elas-CCK2 mice, led to the activation of Src and the ERK pathway. Src was activated upstream of the ERK pathway by the CCK2R in pancreatic tumoral cells and contributed to the proliferative effects mediated by this receptor. In vitro results demonstrated that activation of the Src/ERK pathway by the CCK2R required the NPXXY motif, located within the CCK2R sequence at the end of the 7^th transmembrane domain, and suggested the putative role of Gq in this mechanism. CONCLUSION： Deregulation of the Src/ERK pathway by the CCK2R might represent an early step that contributes to cell proliferation, formation of preneoplastic lesions and pancreatic tumor development.

关键词： Gastrin, Src Pancreas CCK2 receptor

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αV integrin:A new gastrin target in human pancreatic cancer cells

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World Journal of Gastroenterology 2011年第40期17卷 4488-4495页

作者： Celine Cayrol Claudine Bertrand Aline Kowalski-Chauvel Laurence Daulhac Elizabeth Cohen-Jonathan-Moyal Audrey Ferrand catherine seva INSERM UMR1037-Cancer Research Center of Toulouse Paul Sabatier University Toulouse Ⅲ 31432 Toulouse cedex 4 France INSERM U766 Department of pharma-cology Clermont 1 University of Pharmacy 63001 Clermont-Ferrand France

AIM： To analyse αv integrin expression induced by gas- trin in pancreatic cancer ***： αv integrin mRNA expression in human pan- creatic cancer cells was analysed using a ＂cancer genes＂ array and confirmed by real-time reverse transcription- polymerase chain reaction （PCR）. Western blotting and semi-quantitative immunohistochemistry were used to examine protein levels in human pancreatic cancer cell lines and pancreatic tissues, respectively, The role of αv integrin on gastrin-induced cell adhesion was examined using blocking anti-αv integrin monoclonal antibodies. Adherent cells were quantified by staining with crystal ***： Using a ＂cancer genes＂ array we identi- fied c^v integrin as a new gastrin target gene in human pancreatic cancer cells. A quantitative real-time PCR approach was used to confirm αv integrin gene expression. We also demonstrate that Src family kinases and the PI 3-kinase, two signalling pathways specifically activated by the CCK-2 receptor （CCK2R）, are involved in gastrin-mediated αv integrin expression. In contrast, inhibition of the ERK pathway was without any effect on αv integrin expression induced by gastrin. Our results also show that gastrin modulates cell adhesion via αv integrins. Indeed, in vitro adhesion assays performed on fibronectin show that gastrin significantly increases adhesion of pancreatic cancer cells. The use of blocking anti-αv integrin monoclonal antibodies completely reversed the increase in cell-substrate adhesion induced by gastrin. In addition, we showed in vivo that the targeted CCK2R expression in the pancreas of Elas-CCK2 mice, leads to the overexpression of αv integrin. This process may contribute to pancreatic turnout development observed in these transgenic ***： αv integrin is a new gastrin target in pancreatic cancer models and contributes to gastrin effects on cell adhesion.

关键词： v integrin Cell adhesion CCK-2 receptor Gastrin Pancreatic cancer

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