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

A major characteristic of prostate cancer is the elevation of serum levels of prostate-specific antigen (hK3) and hK2, which are tumor markers that correlate with advancing stages of disease. Including hK4, these three kallikrein serine proteases are almost exclusively produced by the prostate. Prostate cancer cells have been recently shown to overexpress protease-activated receptors (PAR), which can be potentially activated by kallikreins and can regulate tumor growth. Here, we show that recombinant hK2 and hK4 activate ERK1/2 signaling of DU-145, PC-3, and LNCaP prostate cancer cells, which express both PAR1 and PAR2. These kallikreins also stimulate the proliferation of DU-145 cells. Pretreatment of hK2 and hK4 with the serine protease inhibitor, aprotinin, blocks the responses in DU-145 cells, and small interfering RNA against PAR1 and PAR2 also inhibits ERK1/2 signaling. To determine which PAR is activated by hK2 and hK4, a cell line that expresses a single PAR, a PAR1 knockout mouse lung fibroblast cell line transfected with PAR1 (KOLF-PAR1) or PAR2 (KOLF-PAR2) was used. hK4 activates both PAR1 and PAR2, whereas hK2 activates PAR2. hK4 generates more phosphorylated ERK1/2 than hK2. These data indicate that prostatic kallikreins (hK2 and hK4) directly stimulate prostate cancer cell proliferation through PAR1 and/or PAR2 and may be potentially important targets for future drug therapy for prostate cancer.
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PMID:Prostate-specific kallikreins-2 and -4 enhance the proliferation of DU-145 prostate cancer cells through protease-activated receptors-1 and -2. 1856 7

Treatment of a light fraction of petroleum treated by metallic catalysis results in a liquid mixture of low molecular weight compounds named LarimshTM (LR). Acute and chronic topical treatment of mice with LR (85 days with 0.1 to 1 mL/animal) indicated no signs of toxicity other than a non dose-dependent, reversible alopecia appearing by the 4th week of topical application. Alopecia completely reversed 2 weeks after treatment withdrawal. Acute oral LR (0.001 to 1 mL; the lowest doses diluted in corn oil as vehicle) gave an estimated LD50 of 21 g/kg (C.I. 95 %: 10.94-41.2 g/kg. LR density = 0.867 g/mL). The antineoplastic action of LR was observed using combined oral and topical treatments in mice; inoculated with a lymphoid leukemia cell line in ascitic phase (International Registry L5178Y); and in terminal patients with prostate cancer (TPCA)--who agreed to receive LR as a compassionate treatment. The survival time for mice was significantly increased when compared with non-treated inoculated mice (51 +/- 2 versus 38 +/- 2 days, p < 0.05, mean +/- SD, N = 6 per group). In 15 patients, LR treatment for 5.5 months (C.I. 95 %: 2.9 to 8.0 months) significantly increased the expected survival time diagnosed to TPCA by their treating physicians (C.I. 95 %: 2.2 to 5.4 versus 12.6 to 41.2 months, p < 0.05) which occurred concomitantly with a significant reduction of blood levels of total prostatic antigen (average 94.5%, range: 67.3 to 99.9%). A theoretical proposal is advanced as a likely explanation of LR actions.
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PMID:Clinical efficacy of a petroleum-derived product (Larimsh) used as compassionate treatment in patients with terminal prostate cancer. 1860 53

The prostate produces several proteases, the most abundant ones being kallikrein-related peptidase 3 (KLK3, PSA) and KLK2 (hK2), which are potential targets for tumor imaging and treatment. KLK3 expression is lower in malignant than in normal prostatic epithelium and it is further reduced in poorly differentiated tumors, in which the expression of KLK2 is increased. KLK3 has been shown to inhibit angiogenesis, whereas KLK2 may mediate tumor growth and invasion by participating in proteolytic cascades. Thus, it may be possible to control prostate cancer growth by modulating the proteolytic activity of KLK3 and KLK2. We have developed peptides that very specifically stimulate the activity of KLK3 or inhibit that of KLK2. Using these peptides we have established peptide-based methods for the determination of enzymatically active KLK3. The first-generation peptides are unstable in vivo and are rapidly cleared from the circulation. Currently we are modifying the peptides to make them suitable for in vivo applications. We have been able to considerably improve the stability of KLK2-binding peptides by cyclization. In this review we summarize the possible roles of KLK3 and KLK2 in prostate cancer and then concentrate on the development of peptides that modulate the activity of these proteases.
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PMID:Development of peptides specifically modulating the activity of KLK2 and KLK3. 1862 44

Prostate-specific antigen (PSA), considered only an established marker for the detection of prostate cancer, has been identified as a member (hK3) of the human kallikrein family of serine proteases and now, it is known that PSA is not specific to prostate, semen, and gender. Increased PSA serum levels have been reported also in cardiovascular patients and both elevated as well as diminished PSA have been reported during acute myocardial infarction (AMI). Preliminary observations have concluded that when elevation of prostate-specific antigen occurs during AMI, it seems to relate to a higher occurrence of major adverse cardiac events and that coronary lesions are frequent and often more severe than when a diminution of PSA occurs. Large studies need to be done to confirm these preliminary results but the journey of PSA could be longer than expected.
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PMID:Prostate-specific antigen kallikrein: from prostate cancer to cardiovascular system. 1936 57

The prostate produces high levels of prostate-specific antigen (PSA, also known as kallikrein-related peptidase 3, KLK3), which is a potential target for tumor imaging and treatment. Although serum PSA levels are elevated in prostate cancer, PSA expression is lower in malignant than in normal prostatic epithelium and it is further reduced in poorly differentiated tumors. PSA has been shown to inhibit angiogenesis both in in vitro and in vivo models. In this review we focus on our recent studies concerning the mechanism of the antiangiogenic function of PSA. We have recently shown that the antiangiogenic activity of PSA is related to its enzymatic activity. Inactive PSA isoforms do not have antiangiogenic activity as studied by a human umbelical vein endothelial cell (HUVEC) tube formation model. Furthermore, inhibition of PSA, either by a monoclonal antibody or small molecule inhibitors abolishes the effect of PSA, while a peptide that stimulates the activity of PSA enhances the antiangiogenic effect. We have analyzed changes in gene expression associated with the PSA induced reduction of tube formation in the HUVEC model. Several small changes were observed and they were found to be opposite to those associated with tube formation. Taken together, these studies suggest that PSA exerts antiantiogenic activity related to its enzymatic activity. Thus it might be associated with the slow growth of prostate cancer.
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PMID:Antiangiogenic properties of prostate-specific antigen (PSA). 1955 56

Human prostate produces kallikrein-related peptidase 3 (KLK3, also known as prostate specific antigen), which is widely used as a prostate cancer marker. Proteolytically active KLK3 has been shown to inhibit angiogenesis and its expression decreases in poorly differentiated tumors. Thus, it may be possible to control prostate cancer growth with agents that stimulate the proteolytic activity of KLK3. We have earlier developed synthetic peptides, which bind specifically to KLK3 and promote its proteolytic activity. These peptides are cyclic, all containing a disulfide bridge between the N- and C-terminal cysteines. To increase the in vivo stability of the KLK3-stimulating peptide B-2, we made differently cyclized analogues by replacing both terminal cysteines and the disulfide bridge between them. A replacement consisting of gamma-amino butyric acid and aspartic acid, where the amino group from the former was linked to the main chain carboxyl group of the latter, was found to be, at high concentrations, more active than the B-2 peptide. Furthermore, as compared to the parent peptide, this analog had an improved stability in plasma and against the enzymatic degradation by KLK3. In addition, the series of analogues also provided valuable information of the structure-activity relationships of the B-2 peptide.
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PMID:Mimetics of the disulfide bridge between the N- and C-terminal cysteines of the KLK3-stimulating peptide B-2. 1996 19

The role of prostate-specific antigen (PSA) or kallikrein-related peptidase 3 (KLK3) as a biomarker for prostate cancer is well known; however, the precise physiological role of it's serine protease activity in prostate cancer remains a mystery. PSA is produced at high levels by both androgen-dependent and -independent prostate cancers. Studies have documented high levels of active PSA in the milieu surrounding osseous and soft tissue metastases. This evidence, coupled with growing experimental evidence, suggests that PSA plays an important role in the pathobiology of prostate cancer. These observations support the development of PSA-selective inhibitors as useful tools for the targeted treatment and imaging of prostate cancer. Here, we review the research that has been conducted to date on developing selective inhibitors for PSA. The different approaches used to determine PSA substrate specificity and for creating inhibitors are discussed. In addition, the unique active site characteristics of PSA and how these motifs aided our research in developing PSA targeted agents are highlighted.
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PMID:Prostate-specific antigen: an overlooked candidate for the targeted treatment and selective imaging of prostate cancer. 2018 Jun 48

Genome-wide association studies have identified genetic markers in kallikrein-related peptidase 3 (KLK3) associated with prostate cancer. However, some of these markers are also associated with prostate-specific antigen (PSA) levels, so it is unclear whether the polymorphisms are causal or if the association with risk is solely due to detection bias through PSA screening. PSA is a biologically active serine protease, cleaving insulin-like growth factor-binding protein. We examined the association of single-nucleotide polymorphisms (SNPs) in KLK3 with prostate cancer risk, disease-specific survival and pre-diagnostic PSA levels in a case-control study nested within the Physicians' Health Study, which began in 1982, with over 27 years of follow-up. We genotyped SNPs spanning the entire KLK3 locus to capture common variation at high resolution. Six polymorphisms were significantly associated with prostate cancer incidence (P < 0.05); the odds ratios per minor allele ranged from 0.88 to 0.73. For four of these, the odds ratios were lower when restricting to cases diagnosed in the pre-PSA screening era (before 1989). The four alleles significantly associated with lower PSA levels were also associated with lower prostate cancer risk. KLK3 variants were not significantly associated with stage at diagnosis, risk of lethal cancer or survival. Our results suggest that detection bias due to the association of KLK3 variants with PSA levels cannot completely explain the association with prostate cancer risk. Understanding the mechanism by which genetic variation in KLK3 affects prostate cancer risk has important implications for study of the biological role of PSA in prostate tumorigenesis.
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PMID:Association of KLK3 (PSA) genetic variants with prostate cancer risk and PSA levels. 2142 45

Human prostate-specific antigen (PSA or human kallikrein-related peptidase 3) present in small quantities in the sera of healthy men becomes elevated in prostate cancer (PCa) and other prostate disorders. The ability to identify the free PSA fraction associated with PCa could increase the reliability of the PSA diagnostic test. Here we present the crystal structure of human PSA from seminal fluid in a sandwich complex with two monoclonal antibodies (mAbs). MAb 5D5A5 captures total PSA with exceptionally high affinity, and mAb 5D3D11 selectively discriminates between free PSA subforms that are more abundant in sera from patients with PCa. Although the antigen is not of seric origin, several insights into cancer diagnosis can be discerned from this complex. MAb 5D3D11 recognizes a PSA conformation different from that previously reported. Interacting with the kallikrein loop, the PSA N-linked glycan attached to asparagine 61 is an uncommonly complex sialated triantennary chain. O-linked glycosylation is observed at threonine 125. The description of how PSA subforms in prostatic fluid can be discriminated using pairs of antibodies is a first step in the design of new strategies that are capable of real discrimination among PSA subforms, which will lead to the formulation of more reliable diagnostic tests. In a companion article [Muller, B. H., Savatier, A., L'Hostis, G., Costa, N., Bossus, M., Michel, S., et al. (2011). In vitro affinity maturation of an anti-PSA antibody for prostate cancer diagnostic assay. J. Mol. Biol.], we describe engineering efforts to improve the affinity of mAb 5D3D11, a first step towards such goal.
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PMID:Crystal structure of human prostate-specific antigen in a sandwich antibody complex. 2203 82

The requirement for high-performance reporter probes in real-time detection of polymerase chain reaction (PCR) has led to the use of time-resolved fluorometry of lanthanide chelates. The aim of this study was to investigate the applicability of the principle of lanthanide chelate complementation (LCC) in comparison with a method based on hydrolysis enhancement and quenching of intact probes. A real-time reverse transcription (RT) PCR assay for kallikrein-related peptidase 3 (KLK3, model analyte) was developed by using the LCC detection method. Both detection methods were tested with a standard series of purified PCR products, 20 prostatic tissues, 20 healthy and prostate cancer patient blood samples, and female blood samples spiked with LNCaP cells. The same limit of detection was obtained with both methods, and two cycles earlier detection with the LCC method was observed. KLK3 messenger RNA (mRNA) was detected in all tissue samples and in 1 of 20 blood samples identically with both methods. The background was 30 times lower, and the signal-to-background (S/B) ratio was 3 times higher, when compared with the reference method. Use of the new reporter method provided similar sensitivity and specificity as the reference method. The lower background, the improved S/B ratio, and the possibility of melting curve analysis and single nucleotide polymorphism (SNP) detection could be advantages for this new reporter probe.
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PMID:Lanthanide chelate complementation and hydrolysis enhanced luminescent chelate in real-time reverse transcription polymerase chain reaction assays for KLK3 transcripts. 2408 79


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