Abstract
Prostate-specific antigen (PSA or kallikrein-related peptidase-3, KLK3) exerts chymotrypsin-like proteolytic activity. The main biological function of PSA is the liquefaction of the clot formed after ejaculation by cleavage of semenogelins I and II in seminal fluid. PSA also cleaves several other substrates, which may explain its putative functions in prostate cancer and its antiangiogenic activity. We compared the proteolytic efficiency of PSA towards several protein and peptide substrates and studied the effect of peptides stimulating the activity of PSA with these substrates. An endothelial cell tube formation model was used to analyze the effect of PSA-degraded protein fragments on angiogenesis. We showed that PSA degrades semenogelins I and II much more efficiently than other previously identified protein substrates, e.g., fibronectin, galectin-3 and IGFBP-3. We identified nidogen-1 as a new substrate for PSA. Peptides B2 and C4 that stimulate the activity of PSA towards small peptide substrates also enhanced the proteolytic activity of PSA towards protein substrates. Nidogen-1, galectin-3 or their fragments produced by PSA did not have any effect on endothelial cell tube formation. Although PSA cleaves several other protein substrates, in addition to semenogelins, the physiological importance of this activity remains speculative. The PSA levels in prostate are very high, but several other highly active proteases, such as hK2 and trypsin, are also expressed in the prostate and may cleave protein substrates that are weakly cleaved by PSA.
Highlights
Proteases have a significant influence on tumor growth, invasion and formation of metastases [1]
By using an endothelial cell tube formation model, we have shown that the enzymatic activity of Prostate-Specific Antigen (PSA) is essential for this activity [23]
As nidogen-1 and galectin-3 have been associated with angiogenesis, we studied whether they or their proteolytic fragments would affect angiogenesis in an endothelial cell tube formation model
Summary
Proteases have a significant influence on tumor growth, invasion and formation of metastases [1]. The known physiological function of PSA is degradation of the gel-forming proteins semenogelins I and II in semen after ejaculation [16]. This leads to liquefaction of the seminal clot and the release of motile sperm, enabling the spermatozoa to travel through the female reproductive tract [17,18]. Several other functions have been suggested for PSA, most of which depend on its proteolytic activity [8,9] These proposed functions have mainly been studied using in vitro methods and it is not known whether they are relevant for prostate cancer development or normal physiology
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