Gastrin-cholecystokininB receptor expression in AGS cells is associated with direct inhibition and indirect stimulation of cell proliferation via paracrine activation of the epidermal growth factor receptor

Background: Activation of the gastrin-cholecystokininB (CCKB) receptor stimulates cell proliferation and increases production of ligands for the epidermal growth factor receptor (EGF-R). Aims: To determine the role of gastrin-CCKB activation in stimulation of cell proliferation via paracrine activation of EGF-R. Methods: AGS cells were transfected with the gastrin-CCKB receptor (AGS-GR cells) or with green fluorescent protein (AGS-GFP cells). Proliferation was determined by [3H] thymidine incorporation, flow cytometry, and cell counting. Results: Gastrin inhibited proliferation of AGS-GR cells by delaying entry into S phase. However, when AGS-GR cells were cocultured with AGS-GFP cells, gastrin stimulated proliferation of the latter. Immunoneutralisation and pharmacological studies using metalloproteinase and kinase inhibitors indicated that the proliferative response was mediated by paracrine stimulation of EGF-R and activation of the mitogen activated protein kinase pathway through release of heparin binding EGF. Conclusions: Gastrin can directly inhibit, and indirectly stimulate, proliferation of gastric AGS cells.