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++ influx operating through nifedipine-dependent and -independent Ca++ channels. Both influxes are necessary for reloading the agonist-sensitive Cai++ pools. In parallel, we demonstrated that nifedipine at doses of 1 microM and 3 microM preferentially blocked the increase in cell number elicited by 10 nM gastrin and 0.1 microM 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.
Bertrand
V
V
INSERM U 151, Institut Fédératif de Recherches Louis Bugnard, CHU Rangueil, Toulouse, France.
Bastié
M J
MJ
Vaysse
N
N
Pradayrol
L
L
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005755:Gastrins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007700:Kinetics; D009543:Nifedipine / Q000494:pharmacology; D010190:Pancreatic Neoplasms; D051381:Rats; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D005755:Gastrins; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014700:Verapamil; D009543:Nifedipine; D002118:Calcium