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.
McDonnel
A C
AC
Reproductive Biology Program, Department of Animal Science, University of Wyoming, Laramie 82071, USA.
Murdoch
W J
WJ
D000230:Adenocarcinoma / Q000188:drug therapy*; D002462:Cell Membrane / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006062:Gonadotropins / Q000494:pharmacology; D006801:Humans; D015735:Mifepristone / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011374:Progesterone / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors; D013739:Testosterone / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D006062:Gonadotropins; D011980:Receptors, Progesterone; D015735:Mifepristone; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol; D014568:Urokinase-Type Plasminogen Activator