ENHANCED C-JUN ACTIVITY ALTERS RESPONSIVENESS TO MEDROXYPROGESTERONE ACETATE IN ISHIKAWA HUMAN ENDOMETRIAL CARCINOMA-CELLS

The involvement of altered c-jun activity in medroxyprogesterone aceta te (MPA)-induced growth responses in human endometrial carcinoma cells is examined in this paper. Under conditions of (MPA)-induced growth i nhibition, c-jun mRNA and protein levels are decreased in Ishikawa cel ls. This decrease is accompanied by an overall decrease in endogenous AP-1 activity in these cells. Only a transient decrease in c-jun mRNA level without any effect on endogenous AP-1 activity is seen in HEC-50 human endometrial carcinoma cells after MPA treatment. Increased expr ession and activity of c-jun was achieved in Ishikawa cells by transie nt transfection of Rous sarcoma virus (RSV)-c-jun alone or RSV-c-jun p lus AP-1 binding sites (5x-4-beta-phorbol 12-myristate 13-acetate resp onse element-thymidine kinase-chloramphenicol acetyltransferase), resp ectively. These treatments were accompanied by an increase in cell num bers due to MPA treatment in Ishikawa cells. In contrast, MPA treatmen t of mock-transfected, RSV-jun-B-transfected, or 5x-4 beta-phorbol 12- myristate 13-acetate response element-thymidine kinase-chloramphenicol acetyltransferase alone transfected Ishikawa cells resulted in the ex pected decrease in cell numbers. The data presented in this paper are consistent with the hypothesis that altered c-jun activity in a target cell can alter proliferative responsiveness to MPA and suggest that s uch a mechanism may be associated with resistance to hormonal manipula tive therapies used in the treatment of both human breast and endometr ial cancer.