Glucocorticoid modulation of plasminogen activators and of one of their inhibitors in the human mammary carcinoma cell line MDA-MB-231.
In cultures of the human mammary carcinoma-derived cell line MDA-MB-231, plasminogen activator (PA) activity was reduced substantially following treatment with the glucocorticoid dexamethasone. These cells produced urokinase-type PA (u-PA) and tissue-type PA (t-PA), and both enzymes were decreased in dexamethasone-treated cultures. The drop in u-PA activity was associated with a decrease in the synthesis of single-chain pro-u-PA and in the concentration of u-PA messenger RNA; however, the decrease in u-PA activity was more extensive than could be accounted for by inhibition of enzyme synthesis only, suggesting that postsynthetic events were also involved. The comparatively small dexamethasone-induced decrease in t-PA activity was not associated with a change in the concentration of t-PA messenger RNA. Hence, the two PA genes are differentially regulated by the same hormone. MDA-MB-231 cells also produced a PA-specific inhibitor related to that produced by bovine aortic endothelial cells (PAI-1). This inhibitor was present in two forms: one functionally active, and the other which required activation by sodium dodecyl sulfate; both forms were increased in cultures exposed to dexamethasone. Thus, glucocorticoid-induced inhibition of PA activity in these cells results from a decrease in u-PA synthesis and a concomitant increase in the production of a PA inhibitor.
D001943:Breast Neoplasms / Q000201:enzymology*; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015849:Plasminogen Inactivators; D011480:Protease Inhibitors / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D015849:Plasminogen Inactivators; D011480:Protease Inhibitors; D012333:RNA, Messenger; D003907:Dexamethasone; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator