Inhibition of gastrin‐induced proliferation of AR4–2j cells by calcium channel antagonists

The exact intracellular mechanisms by which gastrin enhances the proliferation of AR4–2J cells, a tumor pancreatic acinar cell line, are not precisely known. Calcium has long been considered as an intracellular signal involved in growth‐regulatory control of many cell types. Moreover, Ca ++ channel blockers show growth‐suppressing effects in most proliferating cells. In the present study, we analyzed the role of nifedipine, a voltage‐dependent Ca ++ channel antagonist, on AR4–2J cells which possess well‐defined voltage‐dependent Ca ++ channels. The results showed that 10 nM gastrin induced a transient rise in intracellular calcium (Ca ++ ), followed by a sustained phase which was dependent upon a Ca ++ influx operating through nifedipine‐dependent and‐independent Ca ++ channels. Both influxes are necessary for reloading the agonist‐sensitive Ca, ++ pools. In parallel, we demonstrated that nifedipine at doses of I μM and 3 μM preferentially blocked the increase in cell number elicited by 10 nM gastrin and 0.1 μM Bay K 8644, a Ca ++ channel agonist, suggesting that voltage‐sensitive Ca ++ channel activity was required for gastrin‐stimulated mitogenesis. Moreover, nifedipine had no effect on the proliferation of AR4–2J cells growing in serum‐free medium, indicating that this drug did not simply exert a toxic effect. Therefore, Ca ++ influx through voltage‐dependent Ca ++ channels might be an important initial step representing a component of a synergistic cooperation between different signal transduction pathways involved in gastrin‐regulated growth.