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

Oncogene. 2002 Oct 31;21(50):7656-70. doi: 10.1038/sj.onc.1205999.


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 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / pharmacology
  • Adherens Junctions / drug effects
  • Adherens Junctions / metabolism
  • Animals
  • Benzodiazepinones / pharmacology
  • Cadherins / drug effects
  • Cadherins / metabolism
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology*
  • Cell Movement / physiology
  • Cells, Cultured
  • Dogs
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Gastrins / metabolism*
  • Gastrins / pharmacology
  • Humans
  • Kidney / cytology
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism
  • Phenylurea Compounds / pharmacology
  • Phosphatidylinositol 3-Kinases / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Receptor, Cholecystokinin B
  • Receptors, Cholecystokinin / antagonists & inhibitors
  • Receptors, Cholecystokinin / drug effects
  • Receptors, Cholecystokinin / genetics
  • Receptors, Cholecystokinin / metabolism*
  • Transfection
  • Vinculin / drug effects
  • Vinculin / metabolism
  • src-Family Kinases / drug effects
  • src-Family Kinases / metabolism


  • Acetamides
  • Benzodiazepinones
  • Cadherins
  • Gastrins
  • Phenylurea Compounds
  • Receptor, Cholecystokinin B
  • Receptors, Cholecystokinin
  • Vinculin
  • L 365260
  • RP 72540
  • Phosphatidylinositol 3-Kinases
  • src-Family Kinases
  • Mitogen-Activated Protein Kinases