E. Yoshida et al., THROMBIN STIMULATES EXPRESSION OF THE RECEPTOR FOR UROKINASE-TYPE PLASMINOGEN-ACTIVATOR IN DU-145 PROSTATE-CANCER CELLS, Fibrinolysis & proteolysis, 11(3), 1997, pp. 147-154
Coagulants, including thrombin, have been found in many tissues, inclu
ding tumor cells, but their significance is not fully understood. Rece
ntly, the expression of the receptor (uPAR) for urokinase-type plasmin
ogen activator (uPA) and of uPA by many cells has been found to regula
te pericellular proteolysis which is essential for cell migration, it
is well correlated with tumor invasiveness. We studied the effect of t
hrombin on the expression of uPAR in the human prostate cancer cell li
ne, DU-145. Human a-thrombin added to a confluent cultures caused a do
se-dependent increase in [I-125]-pro-uPA binding capacity of DU-145 ce
lls. Incubation with 2 U/ml thrombin for 16 h resulted in an increase
in the number of uPAR from 10.3 +/- 1.6 x 10(4) to 25.4 +/- 3.3 x 10(4
)/cell, and in an increase in Kd of 0.4 +/- 0.17 nM to 1.0 +/- 0.32 nM
. Northern blot analysis showed an increase in the level of uPAR mRNA,
which reached a maximum of 5-fold. Thrombin treated with phenylalanyl
-prolyl-arginylchloromethylketone and hirudin did not produce the effe
ct on uPAR expression, nor did Factor Xa. This thrombin effect can als
o be produced by a thrombin receptor activating peptide, indicating th
at DU-145 cells have specific thrombin receptors and thrombin acts thr
ough its activation. Thrombin had no detectable effect on the expressi
on of uPA and plasminogen activator inhibitor type-1. An acceleration
of the activation of plasminogen was observed in the presence of throm
bin-stimulated DU-145 cells, indicating a functional consequence of th
rombin stimulation. These findings suggest an important role of thromb
in in the regulation of invasive ability of tumor cells through the in
duction of uPAR expression.