Glucocorticoid sensitivity of OVCA 433 human ovarian carcinoma cells: inhibition of plasminogen activators, cell growth, and morphological alterations.
OVCA 433 human ovarian carcinoma cells secrete large amounts of plasminogen activator (PA), which consists of immunologically identifiable urokinase (UK) and tissue-type PA (tPA). Total extracellular PA activity is 95% inhibited by treatment of cells with 1 X 10(-7) M dexamethasone (Dex) for 3 days. This inhibition is both time and concentration dependent, with half-maximal inhibition occurring after 1.5 days with 1 X 10(-7) M Dex, or with 1 X 10(-9) M Dex for 3 days, respectively. Interestingly, the loss of UK activity precedes the loss of tPA activity, such that half-maximal inhibition of the two PA types occurs at 1 and 2 days, respectively. Dex treatment leads to approximately 50% inhibition of cell growth and pronounced morphological alterations, including marked enlargement, flattening, and multinucleation. Treatment of the cells with other classes of steroid hormones, i.e., estrogens, progestins, androgens, and mineralocorticoids, is without effect on UK and tPA activities, cell growth, or morphology. OVCA 433 cells contain about 14,000 nuclear glucocorticoid receptors (GR) per cell (measured at 37 degrees C), with an average affinity (Kd) for [3H]Dex of 6.6 X 10(-9) M. Only active glucocorticoids compete with [3H]Dex for nuclear GR binding sites. Our results demonstrate steroid-specific glucocorticoid responsiveness of ovarian carcinoma cells, a tumor cell type not usually considered hormonally responsive. Since almost 90% of ovarian carcinoma tumor biopsies contain GR (M. C. Galli, et al., Cancer (Phila.), 47: 1297-1302, 1981), it is possible that glucocorticoid sensitivity could be exploited clinically, particularly following the almost universal development of resistance to the chemotherapeutic drugs commonly used in this disease.
D000450:Aldosterone / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D007700:Kinetics; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D013256:Steroids / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D013256:Steroids; D000450:Aldosterone; D003907:Dexamethasone; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D006854:Hydrocortisone