Non-genomic effects of progestins--inhibition of cell growth and increased intracellular levels of cyclic nucleotides

The anti-proliferative effect of progestins was studied in human transformed cell lines from the uterine cervix (C-4I, C33A and Me-180). Progestins caused a concentration-dependent inhibition of proliferation. The maximum tested concentration (2.6-3.2 microM) inhibited C-4I cell growth by the following order of potency: progesterone (56%) > medroxyprogesterone (38%) > megestrol acetate (25%). The sensitivity, expressed as I(25) (the concentration that caused 25% inhibition of growth), showed the same order: progesterone (7.7 nM) > medroxyprogesterone (78 nM) > megestrol acetate (570 nM). The intracellular levels of cGMP and cAMP were elevated and the cellular export of these cyclic nucleotides was inhibited by a similar order of potency. The C-4I cell line was devoid of progesterone-, estrogen-, androgen- and glucocorticoid-receptors. In addition, the antiprogestins mifepristone, onapristone and ZK-112993 did not block the anti-proliferative effect of progesterone. On the other hand, antiprogestins (2.3 nM) appeared to have some progesterone-like ("mimetic") activity with inhibition of C-4I cell growth; mifepristone (11%), onapristone (12%) and ZK-112993 (16%). The observed effects of progestins and antiprogestins on C-4I cells were also presented in C33A cells (16% androgen receptor positive) and Me-180 cells (22% progesterone receptor positive, 9% androgen receptor positive and 17% glucocorticoid receptor positive). This study suggests that a non-genomic mechanism contributes to the anti-proliferative effect of progestins.