Control of VX2 Carcinoma Cell Growth in Culture by Calcium, Calmodulin, and Prostaglandins

Abstract Based on our in vivo observation that growth of VX 2 carcinoma transplanted in rabbits paralleled development of hypercalcemia, we studied the regulation of VX 2 tumor growth using a clonal cell line isolated from VX 2 tumor (VX 2 -L). VX 2 -L cell growth was dependent on prostaglandins released by the cultured cells into the medium, since indomethacin suppressed VX 2 -L growth, and prostaglandins A 2 , E 1 , E 2 , F 1α , and F 2α stimulated VX 2 -L proliferation. In contrast, prostaglandins D 2 and I 2 inhibited VX 2 -L proliferation. In contrast to previous reports, increases in extracellular calcium concentration promoted VX 2 -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 VX 2 -L growth, prostaglandin production, and hypercalcemia. It is proposed that calcium blockers and anticalmodulin drugs might be powerful anticancer and/or antihypercalcemic agenrts for malignant cells such as VX 2 -L.