ENHANCEMENT OF THE EXPRESSION OF UROKINASE-TYPE PLASMINOGEN-ACTIVATORFROM PC-3 HUMAN PROSTATE-CANCER CELLS BY THROMBIN

The presence of procoagulants and fibrin deposition have been demonstr ated in malignant tumors. Although thrombin, a key enzyme in coagulati on, has other various biological functions, the significance of its pr esence in tumors is not known. We studied the effects of thrombin on t he expression of urokinase-type plasminogen activator (uPA) which is k nown to play a role in tumor invasion, using a human prostate cancer c ell line PC-3. Human alpha-thrombin added to cultures of PC-3 produced a dose-dependent and time-dependent increased secretion of uPA that w as greatest at 3-6 h after exposure to thrombin. Increase in uPA antig en paralleled the increase in mRNA level, which reached a maximum at 4 h. Thrombin showed the maximum effect on uPA expression at a concentr ation 1-2 units/ml. Zymography showed that transient exposure to throm bin induced an increase in fibrinolytic activity which could be quench ed by anti-uPA antibody. The thrombin receptor-activating peptide also caused an increase in uPA protein and mRNA level, indicating the pres ence of the same thrombin specific receptor on PC-3 cells as on platel ets and endothelial cells. Thrombin did not affect the expression of o ther components of the plasminogen activation system, tissue-type plas minogen activator and type-1 plasminogen activator inhibitor, and uPA receptor. These results indicate that thrombin increases uPA expressio n selectively by the stimulation of a functional thrombin receptor on PC-3 cells. Since uPA is known to play a role in pericellular proteoly sis of extracellular matrix, thrombin may be involved in the regulatio n of tumor invasion and metastasis.