Control of VX2 carcinoma cell growth in culture by calcium, calmodulin, and prostaglandins.

Based on our in vivo observation that growth of VX2 carcinoma transplanted in rabbits paralleled development of hypercalcemia, we studied the regulation of VX2 tumor growth using a clonal cell line isolated from VX2 tumor (VX2-L). VX2-L cell growth was dependent on prostaglandins released by the cultured cells into the medium, since indomethacin suppressed VX2-L growth, and prostaglandins A2, E1, E2, F1 alpha, and F2 alpha stimulated VX2-L proliferation. In contrast, prostaglandins D2 and I2 inhibited VX2-L proliferation. In contrast to previous reports, increases in extracellular calcium concentration promoted VX2-L growth not only directly but indirectly through augmentation of prostaglandin E synthesis. Antagonists of the intracellular calcium binding protein calmodulin inhibited cell replication. Increases in extracellular calcium also stimulated production of a nonprostaglandin macromolecular bone-resorbing factor. This factor may account for the hypercalcemia which we were unable to block by indomethacin. These results suggest a close relationship between VX2-L growth, prostaglandin production, and hypercalcemia. It is proposed that calcium blockers and anticalmodulin drugs might be powerful anticancer and/or antihypercalcemic agents for malignant cells such as VX2-L.