High-dose progesterone inhibition of urokinase secretion and invasive activity by SKOV-3 ovarian carcinoma cells: evidence for a receptor-independent nongenomic effect on the plasma membrane.

Urokinase plasminogen activator (uPA) has been implicated in the metastatic potential of ovarian carcinomas of surface epithelial origin. The SKOV-3 human ovarian cancer cell line was tested for uPA secretory responses (enzyme immunoassay of conditioned media) after treatments with sex steroids, human menopausal gonadotropins (hMG), or gonadotropin-releasing hormone (GnRH). Secretion of uPA during a 6-h incubation was unaffected by testosterone, estradiol-17beta, hMG, or GnRH. Progesterone, at supraphysiological concentrations, suppressed uPA secretion; this reaction was not altered by the progesterone receptor antagonist RU486 or the transcriptional inhibitor actinomycin D. It appears that progesterone exerted a direct biophysical effect on the plasma membrane manifested by an interference with shedding of uPA in exocytotic vesicles. Finally, invasion of SKOV-3 cells into Matrigel was inhibited by progesterone. We suggest that progesterone can disrupt the fluid dynamics of plasma membranes and thereby invoke an antitumorigenic action via inhibition of proteolytic secretions.