Stimulation of human chorionic gonadotropin by JAr line choriocarcinoma after inhibition of DNA synthesis

Abstract

Treatment of choriocarcinoma cells (JAr line) for 24 hr with methotrexate, fluorodeoxyuridine, 1-beta-D-arabinofuranosylcytosine, or hydroxyurea, in doses that inhibit DNA synthesis, results in a 2.5- to 12-fold increase in human chorionic gonadotropin (HCG) synthesis. Under the conditions of use, these agents do not significantly depress RNA or protein synthesis. Simultaneous addition of thymidine with methotrexate or fluorodeoxyuridine and of deoxycytidine with 1-beta-D-arabinofuranosylcytosine blocks the HCG stimulation. Despite a rapid inhibition of DNA synthesis, HCG stimulation is gradual and reaches a peak after drug removal. Decline in HCG synthesis is coincident with recovery of DNA synthesis, and there is a positive correlation between the duration of inhibition of DNA synthesis and the amount of HCG increase. Although most of the methotrexate-induced stimulation of HCG synthesis occurs after methotrexate removal, preventing protein synthesis during the exposure to methotrexate abrogates the increase. The stimulation of HCG synthesis by methotrexate is more sensitive to protein synthesis inhibition during the first 12 hr of a 24-hr exposure than it is during the second 12 hr. Thus, in accord with the kinetics, specificity, dose dependence, and protein synthesis requirement, HCG synthesis seems to be stimulated as a direct consequence of inhibition of DNA synthesis, with a requirement for some other protein synthesis-dependent event(s) preceding the stimulation.