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Int J Clin Exp Pathol 2(6),588-598;2009
Original Article
Potential Clinical Importance of the Activation Peptide of Prostate-specific Antigen
Laura M. Voeghtly, Ida B. Thøgersen, Zuzana Valnickova, Kristian W. Sanggaard, Charleen T. Chu, Tim D. Oury and Jan J. Enghild
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA and Center for Insoluble Protein Structures,
Department of Molecular Biology, Science Park, University of Aarhus, Denmark
Received 29 April 2009; Accepted 23 May 2009; Available online 20 June 2009
Abstract: 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-α1-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. (IJCEP904008).
Key Words: PSA, prostate cancer, activation peptide
Full text PDF
Address all correspondence to: Laura M. Voeghtly, Department of Pathology, University of Pittsburgh, 200 Lothrop St, BSTWR W904
Pittsburgh, Pennsylvania 15261. Tel: 412-624-8888; Fax: 412-648-9172; Email: lmn20@pitt.edu
Original Article
Potential Clinical Importance of the Activation Peptide of Prostate-specific Antigen
Laura M. Voeghtly, Ida B. Thøgersen, Zuzana Valnickova, Kristian W. Sanggaard, Charleen T. Chu, Tim D. Oury and Jan J. Enghild
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA and Center for Insoluble Protein Structures,
Department of Molecular Biology, Science Park, University of Aarhus, Denmark
Received 29 April 2009; Accepted 23 May 2009; Available online 20 June 2009
Abstract: 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-α1-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. (IJCEP904008).
Key Words: PSA, prostate cancer, activation peptide
Full text PDF
Address all correspondence to: Laura M. Voeghtly, Department of Pathology, University of Pittsburgh, 200 Lothrop St, BSTWR W904
Pittsburgh, Pennsylvania 15261. Tel: 412-624-8888; Fax: 412-648-9172; Email: lmn20@pitt.edu
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