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Gastrin mediated cholecystokinin-2 receptor activation induces loss of cell adhesion and scattering in epithelial MDCK cells

Oncogene volume 21, pages 7656–7670 (2002)Cite this article

Abstract

The presence of gastrin and CCK-2/gastrin receptors in human preneoplastic and neoplastic lesions of pancreas and colon suggests a role in cancer development. Gastrin's growth-promoting action has been established, but a role in cellular morphogenetic processes promoting tumor invasion has been elusive. Our aim was (i) to investigate whether activation of the CCK-2R affects cellular morphology, intercellular adhesion and motility, as crucial parameters of epithelial differentiation, and (ii) to identify the signaling pathways and mechanisms implicated. Madin-Darby Canine Kidney (MDCK) cells were chosen to generate an epithelial non-tumorigenic model system expressing human CCK-2R. Epithelial differentiation and motility were analysed upon CCK-2R activation using immunocytochemistry and invasion assays. The functionality of adhesion complexes and activity of signaling proteins was determined with biochemical techniques. CCK-2R activation induced cell dissociation and enhanced invasion, preceded by decreased membrane localization of adherens junction molecules and nuclear accumulation of β-catenin. Concomitantly, and requiring the activation of several signaling pathways, catenins were shifted from the cytoskeletal to the cytoplasmic fraction, suggesting the detachment of the cytoskeleton from the adherens complex. These data represent the first evidence for the CCK-2R, regulating cell–cell and cell–substrate adhesion and support a role for CCK-2R in the progression of carcinoma.

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Acknowledgements

We are very grateful to Dr R Kemler (Freiburg, Germany), Dr A Reynolds (Nashville, USA) and Drs Y Le Marchand-Brustel and JF Tanti (Nice, France) for antibodies, Dr H Paris (Toulouse, France) for MDCK cells, and Chantal Escrieut (Toulouse, France) for the PRFEneo plasmid encoding the human CCK-2R. Thanks to Dr P Cochard (Toulouse, France) for assistance with the confocal microscope and to Dr M Haenlin (Toulouse, France) for encouragement during the generation of this work. We thank Dr M Dufresne for critically reading the manuscript and all members of the INSERM unit U531 for their interest and stimulating discussions. This work was supported by funds from INSERM and the ‘Association pour la Recherche contre le Cancer’ Grants #9540 and 5481.

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Authors and Affiliations

  1. Department de Biologie et Pathologie Digestive, Institut National de la Santé et la Recherche Médicale (INSERM) U531,

    Christiane Bierkamp, Aline Kowalski-Chauvel, Stephanie Dehez, Daniel Fourmy, Lucien Pradayrol & Catherine Seva

  2. Institut Louis Bugnard, CHU Rangueil, Toulouse, 31403, France

    Christiane Bierkamp, Aline Kowalski-Chauvel, Stephanie Dehez, Daniel Fourmy, Lucien Pradayrol & Catherine Seva

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  1. Christiane Bierkamp
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Correspondence to Christiane Bierkamp.

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Bierkamp, C., Kowalski-Chauvel, A., Dehez, S. et al. Gastrin mediated cholecystokinin-2 receptor activation induces loss of cell adhesion and scattering in epithelial MDCK cells. Oncogene 21, 7656–7670 (2002). https://doi.org/10.1038/sj.onc.1205999

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