Antiangiogenic properties of prostate-specific antigen (PSA).

The prostate produces high levels of prostate-specific antigen (PSA, also known as kallikrein-related peptidase 3, KLK3), which is a potential target for tumor imaging and treatment. Although serum PSA levels are elevated in prostate cancer, PSA expression is lower in malignant than in normal prostatic epithelium and it is further reduced in poorly differentiated tumors. PSA has been shown to inhibit angiogenesis both in in vitro and in vivo models. In this review we focus on our recent studies concerning the mechanism of the antiangiogenic function of PSA. We have recently shown that the antiangiogenic activity of PSA is related to its enzymatic activity. Inactive PSA isoforms do not have antiangiogenic activity as studied by a human umbelical vein endothelial cell (HUVEC) tube formation model. Furthermore, inhibition of PSA, either by a monoclonal antibody or small molecule inhibitors abolishes the effect of PSA, while a peptide that stimulates the activity of PSA enhances the antiangiogenic effect. We have analyzed changes in gene expression associated with the PSA induced reduction of tube formation in the HUVEC model. Several small changes were observed and they were found to be opposite to those associated with tube formation. Taken together, these studies suggest that PSA exerts antiantiogenic activity related to its enzymatic activity. Thus it might be associated with the slow growth of prostate cancer.