Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human tissue kallikreins (hKs) are a family of fifteen serine proteases. Several lines of evidence suggest that hKs participate in proteolytic cascade pathways. Human kallikrein 5 (hK5) has trypsin-like activity, is able to self-activate, and is co-expressed in various tissues with other hKs. In this study, we examined the ability of hK5 to activate other hKs. By using synthetic heptapeptides that encompass the activation site of each kallikrein and recombinant pro-hKs, we demonstrated that hK5 is able to activate pro-hK2 and pro-hK3. We then showed that, following their activation, hK5 can internally cleave and deactivate hK2 and hK3. Given the predominant expression of hK2 and hK3 in the prostate, we examined the pathophysiological role of hK5 in this tissue. We studied the regulation of hK5 activity by cations (Zn2+, Ca2+, Mg2+, Na2+, and K+) and citrate and showed that Zn can efficiently inhibit hK5 activity at levels well below its normal concentration in the prostate. We also show that hK5 can degrade semenogelins I and II, the major components of the seminal clot. Semenogelins can reverse the inhibition of hK5 by Zn2+, providing a novel regulatory mechanism of its serine protease activity. hK5 is also able to internally cleave insulin-like growth factor-binding proteins 1, 2, 3, 4, and 5, but not 6, suggesting that it might be involved in prostate cancer progression through growth factor regulation. Our results uncover a kallikrein proteolytic cascade pathway in the prostate that participates in seminal clot liquefaction and probably in prostate cancer progression.
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PMID:Human tissue kallikrein 5 is a member of a proteolytic cascade pathway involved in seminal clot liquefaction and potentially in prostate cancer progression. 1651 95

Human kallikrein 2 (hK2) is a serine protease produced by the secretory epithelial cells in the prostate. Because hK2 activates several factors participating in proteolytic cascades that may mediate metastasis of prostate cancer, modulation of the activity of hK2 is a potential way of preventing tumor growth and metastasis. Furthermore, specific ligands for hK2 are potentially useful for targeting and imaging of prostate cancer and for assay development. We have used enzymatically active recombinant hK2 captured by a monoclonal antibody exposing the active site of the enzyme to screen phage display peptide libraries. Using libraries expressing 10 or 11 amino acids long linear peptides, we identified six different peptides binding to hK2. Three of these were shown to be specific and efficient inhibitors of the enzymatic activity of hK2 toward a peptide substrate. Furthermore, the peptides inhibited the activation of the proform of prostate-specific antigen by hK2. Amino acid substitution analyses revealed that motifs of six amino acids were required for the inhibitory activity. These peptides are potentially useful for treatment and targeting of prostate cancer.
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PMID:Novel peptide inhibitors of human kallikrein 2. 1652 22

The high prevalence of osteoblastic bone metastasis in prostate cancer is thought to be attributable to the production of osteoblast-stimulating factors by prostate cancer cells. Prostate-specific antigen (PSA) expression is arguably the most distinctive features of prostate cancer. PSA is a serine protease and an important serological marker for prostate cancer. Expression, secretion, and activation of transforming growth factor-beta (TGF-beta) is induced by PSA, and PSA-induced osteoblastic changes in bone were caused by an autonomous increase in mature osteoblasts and by depletion of the osteoclast population. Osteoblastic changes result from an imbalance between the rate of bone resorption and formation.
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PMID:[Mechanism of osteoblastic bone metastasis of prostate cancer]. 1658 5

Hepsin is a type II transmembrane serine protease that is expressed in normal liver, and at lower levels in kidney, pancreas, and testis. Several studies have shown that hepsin mRNA is significantly elevated in most prostate tumors, as well as a significant fraction of ovarian and renal cell carcinomas and hepatomas. Although the overexpression of mRNA in these tumors has been extensively documented, there has been conflicting literature on whether hepsin plays a role in tumor cell growth and progression. Early literature implied a role for hepsin in human tumor cell proliferation, whereas recent studies with a transgenic mouse model for prostate cancer support a role for hepsin in tumor progression and metastases. To evaluate this issue further, we have expressed an activatable form of hepsin, and have generated a set of monoclonal antibodies that neutralize enzyme activity. The neutralizing antibodies inhibit hepsin enzymatic activity in biochemical and cell-based assays. Selected neutralizing and nonneutralizing antibodies were used in cell-based assays with tumor cells to evaluate the effect of antibodies on tumor cell growth and invasion. Neutralizing antibodies failed to inhibit the growth of prostate, ovarian, and hepatoma cell lines in culture. However, potent inhibitory effects of the antibodies were seen on invasion of ovarian and prostate cells in transwell-based invasion assays. These results support a role for hepsin in tumor cell progression but not in primary tumor growth. Consistent with this, immunohistochemical experiments with a mouse monoclonal antibody reveal progressively increased staining of prostate tumors with advanced disease, and in particular, extensive staining of bone metastatic lesions.
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PMID:Antibodies neutralizing hepsin protease activity do not impact cell growth but inhibit invasion of prostate and ovarian tumor cells in culture. 1658 86

To study the expression and significance of the serine protease Omi/HtrA2 in prostate cancer and benign prostatic hyperplasia. The expression of Omi/HtrA2 was assayed by means of immunohistochemical technique in 41 prostate cancer (Cap), 20 benign prostatic hyperplasia (BPH) and 10 normal prostate (NP) specimens. Omi/HtrA2 expression was positive in 30 (73.17%) prostate cancer specimens, and the positive rate of Omi/HtrA2 was lower in well differentiated than in poorly and moderately differentiated groups (P < 0.05). By contrast, the cells in normal prostate and benign prostatic hyperplasia groups showed no or weak expression of Omi/HtrA2. Prostate cancer cells in vivo may need Omi/HtrA2 expression for apoptosis, and that Omi/HtrA2 expression might be involved in prostate cancer development.
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PMID:Immunohistochemical analysis of Omi/HtrA2 expression in prostate cancer and benign prostatic hyperplasia. 1669 22

Matriptase is an epithelium-derived type II transmembrane serine protease and has been implicated in the activation of substrates such as pro-HGF/SF and pro-uPA, which are likely involved in tumor progression and metastasis. Through screening, we have identified bis-basic secondary amides of sulfonylated 3-amidinophenylalanine as matriptase inhibitors. X-ray analyses of analogues 8 and 31 in complex with matriptase revealed that these inhibitors occupy, in addition to part of the previously described S4-binding site, the cleft formed by the molecular surface and the unique 60 loop of matriptase. Therefore, optimization of the inhibitors included the incorporation of appropriate sulfonyl substituents that could improve binding of these inhibitors into both characteristic matriptase subsites. The most potent derivatives inhibit matriptase highly selective with K(i) values below 5 nM. Molecular modeling revealed that their improved affinity results from interaction with the S4 site of matriptase. Analogues 8 and 59 were studied in an orthotopic xenograft mouse model of prostate cancer. Compared to control, both inhibitors reduced tumor growth, as well as tumor dissemination.
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PMID:Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase. 1682 72

Hepsin, a type II transmembrane serine protease, is strongly up-regulated in prostate cancer. Hepsin overexpression in a mouse prostate cancer model resulted in tumor progression and metastasis, associated with basement membrane disorganization. We investigated whether hepsin enzymatic activity was linked to the basement membrane defects by examining its ability to initiate the plasminogen/plasmin proteolytic pathway. Because plasminogen is not processed by hepsin, we investigated the upstream activators, urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator. Enzymatic assays with a recombinant soluble form of hepsin demonstrated that hepsin did not cleave pro-tissue-type plasminogen activator but efficiently converted pro-uPA into high molecular weight uPA by cleavage at the Lys158-Ile159 (P1-P1') peptide bond. uPA generated by hepsin displayed enzymatic activity toward small synthetic and macromolecular substrates indistinguishable from uPA produced by plasmin. The catalytic efficiency of pro-uPA activation by hepsin (kcat/Km 4.8 x 10(5) m(-1) s(-1)) was similar to that of plasmin, which is considered the most potent pro-uPA activator and was about 6-fold higher than that of matriptase. Conversion of pro-uPA was also demonstrated with cell surface-expressed full-length hepsin. A stable hepsinoverexpressing LnCaP cell line converted pro-uPA into high molecular weight uPA at a rate of 6.6 +/- 1.9 nm uPA h(-1), which was about 3-fold higher than LnCaP cells expressing lower hepsin levels on their surface. In conclusion, the ability of hepsin to efficiently activate pro-uPA suggests that it may initiate plasmin-mediated proteolytic pathways at the tumor/stroma interface that lead to basement membrane disruption and tumor progression.
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PMID:Pro-urokinase-type plasminogen activator is a substrate for hepsin. 1690 24

The relationship between chronic prostatitis and fertility has been disputed for many years. Several groups have shown infection and autoimmune response against prostate antigens could have a deleterious effect on semen quality and fertility. This study was conducted to test the hypothesis that Omi/HtrA2-induced apoptosis in chronic prostatitis could be a mechanism underlying the observed clinical benefit. The Omi/HtrA2 serine protease is a nuclear-encoded mitochondrial protein, which can be released from mitochondria into the cytosol after apoptosis stimuli, inducing apoptosis in caspase-dependent and independent manners. Forty-one patients diagnosed as suffering from chronic prostatitis were included. Healthy normal individuals were included as controls. Human spermatozoa in the semen were purified by Percoll-gradient technique to separate the seminal plasma and other round cells. Measurements for sperm concentration, motility, morphology, proinflammatory cytokines, Omi/HtrA2 mRNA and protein levels in spermatozoa of chronic protatitis patients, were performed accordingly. Significantly increased levels of proinflammatory cytokines were detected in seminal plasma from these prostatitis patients. Omi/HtrA2 mRNA and protein levels were significantly higher in prostatitis men than in normal men. This study shows that chronic prostatitis patients present important alterations in their semen quality parameters, Omi/HtrA2 mRNA and protein levels of spermatozoa. We speculate that the inflammatory process involved may affect male fertility by release of proapoptotic protein Omi/HtrA2.
Prostate Cancer Prostatic Dis 2007
PMID:Reduced semen quality in chronic prostatitis patients that induce the release of apoptotic protein Omi/HtrA2 from spermatozoa. 1804 64

Human tissue kallikrein 14 (KLK14) is a novel extracellular serine protease. Clinical data link KLK14 expression to several diseases, primarily cancer; however, little is known of its (patho)-physiological role. To functionally characterize KLK14, we expressed and purified recombinant KLK14 in mature and proenzyme forms and determined its expression pattern, specificity, regulation, and in vitro substrates. By using our novel immunoassay, the normal and/or diseased skin, breast, prostate, and ovary contained the highest concentration of KLK14. Serum KLK14 levels were significantly elevated in prostate cancer patients compared with healthy males. KLK14 displayed trypsin-like specificity with high selectivity for P1-Arg over Lys. KLK14 activity could be regulated as follows: 1) by autolytic cleavage leading to enzymatic inactivation; 2) by the inhibitory serpins alpha1-antitrypsin, alpha2-antiplasmin, antithrombin III, and alpha1-antichymotrypsin with second order rate constants (k(+2)/Ki) of 49.8, 23.8, 1.48, and 0.224 microM(-1) min(-1), respectively, as well as plasminogen activator inhibitor-1; and 3) by citrate and zinc ions, which exerted stimulatory and inhibitory effects on KLK14 activity, respectively. We also expanded the in vitro target repertoire of KLK14 to include collagens I-IV, fibronectin, laminin, kininogen, fibrinogen, plasminogen, vitronectin, and insulin-like growth factor-binding proteins 2 and 3. Our results indicate that KLK14 may be implicated in several facets of tumor progression, including growth, invasion, and angiogenesis, as well as in arthritic disease via deterioration of cartilage. These findings may have clinical implications for the management of cancer and other disorders in which KLK14 activity is elevated.
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PMID:Expression and functional characterization of the cancer-related serine protease, human tissue kallikrein 14. 1711 Mar 83

Prostate cancer cells, like normal prostate epithelial cells, produce high levels of the differentiation marker and serine protease prostate-specific antigen (PSA). PSA is used extensively as a biomarker to screen for prostate cancer, to detect recurrence following local therapies, and to follow response to systemic therapies for metastatic disease. While much is known about PSA's role as a biomarker, only a relatively few studies address the role played by PSA in the pathobiology of prostate cancer. Autopsy studies have documented that not only do prostate cancer cells maintain production of high amounts of PSA but they also maintain the enzymatic machinery required to process PSA to an enzymatically active form. A variety studies performed over the last 10 years have hinted at a role for PSA in growth, progression, and metastases of prostate cancer. A fuller understanding of PSA's functional role in prostate cancer biology, however, has been hampered by the lack of appropriate models and tools. Therefore, the purpose of this review is not to address issues related to PSA as a biomarker. Instead, by reviewing what is known about the genetics, biochemistry, and biology of PSA in normal and malignant prostate tissue, insights may be gained into the role PSA may be playing in the pathobiology of prostate cancer that can connect measurement of this biomarker to an understanding of the underlying etiology and progression of the disease.
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PMID:Does PSA play a role as a promoting agent during the initiation and/or progression of prostate cancer? 1714 82


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