Mechanisms of calcitonin induction of prolonged activation of adenylate cyclase in human cancer cells.

Four human cancer cell lines (MCF 7, T 47D, ZR 75 and BEN), each of which possess calcitonin-responsive adenylate cyclase, have been investigated. Pre-treatment of cells with calcitonin resulted in two effects on their adenylate cyclase. First, the ability of adenylate cyclase to respond to further stimulation by calcitonin was reduced. Secondly, membranes from calcitonin-preincubated cells had increased activity of adenylate cyclase compared with control membranes, the activated state not only surviving washing and cell-disrupting steps but persisting for some hours after the removal of hormone from the incubation medium. This phenomenon has therefore been termed "persistent activation" and may be peculiar to the action of calcitonin. It is dose dependent and is seen with calcitonins of various origins (sCT, hCT, pCT and [Asu1-7] eCT). When pre-bound hormone was removed from the cell surface by acid washing, adenylate cyclase activities in preincubated membranes fell towards control activities and responsiveness of the enzyme to a second challenge with calcitonin returned. Inhibitors of protein synthesis prevented full recovery from desensitization but had no effect on the return towards control of residual enzyme activity in preincubated membranes. These results are consistent with continued receptor occupancy leading to a persistent activation of adenylate cyclase until internalization of the receptor has occurred.