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First published online 6 February 2003
doi: 10.1242/jcs.00321
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Research Article |
1 Laboratoire de Signalisation Cellulaire Normale et Tumorale, EA MNRT 2995,
Faculté de Pharmacie, 15 Avenue C. Flahault, 34093 Montpellier,
France
2 University of Melbourne, Department of Surgery, Austin Hospital, Melbourne,
VIC 3084, Australia
3 CNRS UPR 1086, Route de Mende, 34293 Montpellier, France
* Author for correspondence (e-mail: fhollande{at}ww3.pharma.univ-montp1.fr)
Accepted 12 December 2002
Adhesion between neighbouring epithelial cells is a crucial and tightly controlled process. In the gastrointestinal tract, the integrity of cell-cell contacts is essential for the regulation of electrolyte absorption and for the prevention of tumour metastasis. We recently showed that migration of the gastric epithelial cell line IMGE-5 is stimulated by the nonamidated form of the hormone gastrin17. Here, we examine the effect on cell-cell adhesion of the prohormone progastrin, the concentration of which is increased in the plasma of patients with colorectal carcinoma.
Progastrin induced the dissociation of both tight junction (TJ) and
adherens junction (AJ) complexes in IMGE-5 cells. In progastrin-secreting
DLD-1 human colorectal carcinoma cells, expression of an antisense gastrin
construct restored membrane localisation of zonula occludens-1 (ZO-1),
occludin, ß-catenin and E-cadherin. This restoration was reversed by
treatment with exogenous progastrin. Endogenous or exogenous progastrin also
increased the paracellular flux of mannitol, and induced cell migration of
several gastrointestinal cell lines. In addition, progastrin enhanced Src
tyrosine kinase activity and induced a spatial delocalisation of protein
kinase C
. Using dominant-negative mutants and pharmacological
inhibitors, we showed that the stimulation of Src kinase activity was
essential for the regulation of TJs. By contrast, the dissociation of AJs
involved phosphatidylinositol 3-kinase, partly through the formation of a
complex with protein kinase C. We conclude that separate pathways
mediate the disruption of AJs and TJs by progastrin. Either pathway may
contribute to the co-carcinogenic role of this prohormone in colorectal
carcinoma.
Key words: Tight junctions, ß-catenin, Progastrin, Src, PI3-kinase
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