High-dose progesterone inhibition of urokinase secretion and invasive activity by SKOV-3 ovarian carcinoma cells: evidence for a receptor-independentnongenomic 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 h uman ovarian cancer cell line was tested for uPA secretory responses (enzym e immunoassay of conditioned media) after treatments with sex steroids, hum an menopausal gonadotropins (hMG), or gonadotropin-releasing hormone (GnRH) , Secretion of uPA during a 6-h incubation was unaffected by testosterone, estradiol-17 beta, hMG, or GnRH. Progesterone, at supraphysiological concen trations, suppressed uPA secretion, this reaction was not altered by the pr ogesterone receptor antagonist RU486 or the transcriptional inhibitor actin omycin D. It appears that progesterone exerted a direct biophysical effect on the plasma membrane manifested by an interference with shedding of uPA i n exocytotic vesicles. Finally, invasion of SKOV-3 cells into Matrigel was inhibited by progesterone. We suggest that progesterone can disrupt the flu id dynamics of plasma membranes and thereby invoke an antitumorigenic actio n via inhibition of proteolytic secretions. (C) 2001 Published by Elsevier Science Ltd.