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Prostate‐specific antigen and other prostate‐derived proteases cleave IGFBP‐3, but prostate cancer is not associated with proteolytically cleaved circulating IGFBP‐3
Author(s) -
Koistinen Hannu,
Paju Annukka,
Koistinen Riitta,
Finne Patrik,
Lövgren Janita,
Wu Ping,
Seppälä Markku,
Stenman UlfHåkan
Publication year - 2002
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.10039
Subject(s) - proteases , prostate cancer , trypsin , proteolysis , prostate , prostate specific antigen , kallikrein , endocrinology , biology , medicine , chemistry , cancer research , cancer , biochemistry , enzyme
BACKGROUND Proteolysis of insulin‐like growth factor‐binding proteins (IGFBPs) may increase IGF‐mediated growth stimulation and development of cancer in the organs producing large amounts of proteases, such as the prostate. METHODS We studied proteolysis of IGFBP‐3 by three prostate‐derived proteases, namely prostate specific antigen (PSA), human kallikrein 2 (hK2), and trypsin, and also by native seminal plasma. Cleavage of 125 I‐IGFBP‐3 was studied by SDS–PAGE and autoradiography. We also used two different sandwich‐type IGFBP‐3 immunoassays, called “intact” and “total” IGFBP‐3 assays. These assays differ in their capacity to recognize proteolytically degraded IGFBP‐3. RESULTS HK2, PSA, and trypsin all cleaved IGFBP‐3 at the concentrations normally present in seminal plasma. The IGFBP‐3 cleavage by seminal plasma was inhibited by ZnCl 2 , which strongly inhibits hK2 and PSA, but not by a specific trypsin inhibitor. The IGFBP‐3 fragments resulting from proteolytic cleavage by PSA, hK2, or trypsin were undetectable in the “intact IGFBP‐3 assay,” whereas the “total IGFBP‐3 assay” also detected the proteolytic fragments. No increased fragmentation of IGFBP‐3 was found in serum of 659 men with elevated PSA concentrations, of whom 178 had a proven prostate cancer. Furthermore, the IGFBP‐3 levels were not associated with the PSA concentrations. CONCLUSIONS These results show that, while seminal plasma and prostate‐derived proteases can cleave IGFBP‐3, in patients with prostate cancer the circulating IGFBP‐3 is not significantly proteolyzed by either PSA, hK2, or trypsin. Prostate 50: 112–118, 2002. © 2002 Wiley‐Liss, Inc.