The effects of ATP and histamine on cell proliferation and intracellular calcium concentrations ([Ca2+](i)) were examined in the human ovarian cancer cell line SKOV-3. Micromolar concentrations of ATP induced a biphasic increase in [Ca2+](i) representing a rapid rise to a peak level followed by a smaller but more sustained phase. When influx of extracellular calcium was blocked by calcium chelation td EGTA, the ATP-stimulated rise in [Ca2+](i) was rapid and only monophasic. Histamine, in contrast to ATP, caused only a monophasic rise in [Ca2+](i) both in the presence and absence of external calcium. The histaminergic H-1 receptor antagonist pyrilamine, but not the H-2 receptor antagonist cimetidine, totally blocked rises in [Ca2+](i) caused by histamine. Fetal calf serum (FCS) induced a slow and monophasic increase in [Ca2+](i) in these cells, distinctly different from rises in [Ca2+](i) caused by ATP and histamine. Inclusion of low micromolar concentrations of ATP in the growth medium stimulated proliferation of these cells, while higher concentrations (100 mu M-1 mM) significantly decreased cellular proliferation. Histamine, in micromolar concentrations, also stimulated cell proliferation. From these results it was concluded that the release of intracellularly bound Ca2+ following receptor stimulation is sufficient to induce cellular proliferation in SKOV-3 cells.
