Potential clinical importance of the activation peptide of prostate-specific antigen

Prostate cancer is the second leading cause of cancer death in men. Prostate specific antigen (PSA) is currently the best marker available for screening and monitoring disease recurrence, but its use has limitations. This study investigates the biosynthesis, secretion and activation of PSA in a prostate adenocarcinoma cell line. PSA is secreted as a pro-enzyme containing a seven amino acid activation peptide (APLILSR). Because the activation peptide is removed extracellularly in vivo, we hypothesized that it may be detected in the blood or urine. Activated PSA is a serine protease and reacts rapidly with protease inhibitors in the blood. These protein complexes are removed from the circulatory system by hepatocyte-mediated endocytosis. This rapid clearance likely interferes with detection of PSA in the early stages of prostate cancer. Notably these clearance mechanisms are not considered when PSA levels are determined clinically. We used radio-labeled proteins to determine the clearance of PSA in complex with its inhibitors as well as in vivo clearance of APLILSR. Dot blotting was used to determine the presence of APLILSR in human urine samples. Our data indicates that PSA-alpha1-antichymotrypsin only accumulates in the blood when large amounts of PSA are present and saturate clearance mechanisms. We found that APLILSR is filtered from the bloodstream by the kidney, and is detectable in the urine of patients with prostate cancer, but not controls. We propose that urine detection of the PSA activation peptide may represent a clinically sensitive measure of PSA production/secretion.