Caratterizzazione del sistema attivatore del plasminogeno nella progressione metastatica del cancro prostatico umano

GnRH analogues are used for the treatment of prostate cancer (PCa) because their ability to suppress the activity of the pituitary-testicular axis, with consequent blockade of testosterone production. However, after an initial responsiveness to hormonal deprivation, PCa progresses and then metastatises. It is known that the system of the plasminogen activator (uPA, uPA inhibitors PAI-1/2 and uPA receptor, uPAR) has been involved in the local degradation of the extracellular matrix and PCa progression and metastases. Studies performed in our laboratory have demonstrated the presence of GnRH receptors, suggesting a direct effect of GnRH analogues in inhibiting the proliferation of human PCa cell lines. The aim of this study was to test the effect of an agonist (Leuprolide) and an antagonist (Cetrorelix) of GnRH on uPA/uPAR and PAI-1 expression and activity, on the migratory and invasion capabilities in the two androgen-independent cell lines, DU145 and PC3 cells. The results obtained in DU145 and PC3 cells show that both Leuprolide and Cetrorelix: 1) significantly decrease the enzymatic activity of uPA; 2) induce a marked decrease of uPA and a significant increase of PAI-1 protein levels; 3) increase the presence of soluble uPAR in the cell media; 4) decrease the migratory and invasion capabilities. In conclusions, GnRH analogues might interfere with the mechanisms of metastatic progression of human androgen-independent PCa by inhibiting the activity of the plasminogen activator system.