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++)(i) followed by a sustained phase which was dependent upon a Ca++ channels. Both influexes are necessary for reloading the agonist-sensitive Ca-i(++) pools. In parallel, we demonstrated that nifedipine at doses of 1 mu M and 3 mu M preferentially blocked the increase in cell number elicited by 10 nM gastrin and 0.1 mu M bay K8644, a Ca++ influx through voltage-dependent 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. (C) 1994 Wiley-Liss, Inc.