Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1519176 (PSA)
 5,490 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human tissue kallikreins (genes, KLKs; proteins, hKs) are a subgroup of hormonally regulated serine proteases. Two tissue kallikreins, namely hK2 and hK3 (prostate-specific antigen, PSA), are currently used as serological biomarkers of prostate cancer. Human tissue kallikrein 9 (KLK9) is a newly identified member of the tissue kallikrein gene family. Recent reports have indicated that KLK9 mRNA is differentially expressed in ovarian and breast cancer and has prognostic value. Here, we report the production of recombinant hK9 (classic form) using prokaryotic and mammalian cells and the generation of polyclonal antibodies. Total testis tissue mRNA was reverse-transcribed to cDNA, amplified, cloned into a pET/200 TOPO plasmid vector, and transformed into E. coli cells. hK9 was purified and used as an immunogen to generate polyclonal antibodies. Full-length KLK9 cDNA was also cloned in the vector pcDNA3.1 and was expressed in CHO cells. The identity of hK9 was confirmed by mass spectrometry. hK9 rabbit antiserum displayed no cross-reactivity with other tissue kallikreins and could specifically recognize E. coli- and CHO-derived hK9 on Western blots. hK9 was mainly detected in testis and seminal vesicles by Western blotting. The reagents generated here will help to define the physiological role of this tissue kallikrein and its involvement in human disease.
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PMID:Human tissue kallikrein 9: production of recombinant proteins and specific antibodies. 1680 Jul 34

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

The introduction of total prostate-specific antigen (tPSA) testing in serum has revolutionized the detection and management of men with prostate cancer. This review will highlight some of the exciting new developments in the field of prostate cancer screening in general and from our SPORE research program at Memorial-Sloan Kettering Cancer Center. First, it is important to understand that the inherent variability of tPSA levels affects the interpretation of any single results. Total variation in tPSA includes both analytical (i.e., pre-analytical sample handling, laboratory processing, assay performance, and standardization) and biological variation (i.e., metabolism, renal elimination, medication, physical and sexual activity, size and integrity of the prostate). Second, recent evidence demonstrates that no single tPSA cut-off separates men at high risk for prostate cancer from men at low risk or men with "significant" (high grade, high volume) cancer from those with low grade, indolent cancer. Taken together with a man's age, family history, ethnicity, and digital rectal exam results, tPSA levels add to the overall estimate of the risk of cancer, allowing men to share in the decision about a biopsy. Third, men who will eventually develop prostate cancer have increased tPSA levels years or decades before the cancer is diagnosed. These tPSA levels may reflect the long duration of prostate carcinogenesis and raise the question about a causal role for tPSA in prostate cancer development and progression. Total prostate-specific antigen measurements before age 50 could help risk stratify men for intensity of prostate cancer screening. Fourth, enhancing the diagnostic accuracy of tPSA, especially its specificity, is of particular importance, since higher specificity translates into fewer biopsies in men not affected by prostate cancer. While tPSA velocity has been shown to improve the specificity of tPSA, its sensitivity is too low to avoid prostate biopsy in a patient with an elevated tPSA level. Moreover, prospective screening studies have reported that tPSA velocity does not add diagnostic value beyond tPSA level. At this time, tPSA velocity appears most useful after diagnosis and after treatment, but its value in screening and prognostication remains to be shown. Finally, while free PSA molecular isoforms and human kallikrein-related peptidase 2 (hK2) hold the promise for detection, staging, prognosis, and monitoring of prostate cancer, evidence from large prospective clinical trials remain to be reported.
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PMID:Screening for prostate cancer: an update. 1904 89

Available chemotherapeutics take advantage of the fast proliferation of cancer cells. Consequently slow growth makes androgen refractory prostate cancer resistant towards available drugs. No treatment is available at the present, when the cancer has developed metastases outside the prostate (T4 stage). Cytotoxins killing cells irrespective of the phase of the cell cycle will be able to kill slowly proliferating prostate cancer cells. Lack of selectivity, however, prevents their use as systemic drugs. Prostate cancer cells secrete characteristic proteolytic enzymes, e.g. PSA and hK2, with unusual substrate specificity. Conjugation of cytotoxins with peptides, which are selective substrates for PSA or hK2, will afford prodrugs, from which the active drug only will be released in close vicinity of the cancer cells. Based on this strategy prodrugs targeted at prostate cancer cells have been constructed and evaluated as potential drugs for prostate cancer. The potency of the thapsigargins as apoptotic agents make these naturally occurring sesquiterpene lactones attractive lead compounds. Intensive studies on structure-activity relationships and chemistry of the thapsigargins have enabled construction of potent derivatives enabling conjugation with peptides. Studies on the mechanism of action of the thapsigargins have revealed that the cytoxicity is based on their ability to inhibit the intracellular sarco-/endoplasmtic calcium pump.
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PMID:A Trojan horse in drug development: targeting of thapsigargins towards prostate cancer cells. 1927 21

Polymorphisms associated with prostate cancer include those in three genes encoding major secretory products of the prostate: KLK2 (encoding kallikrein-related peptidase 2; hK2), KLK3 (encoding prostate-specific antigen; PSA), and MSMB (encoding beta-microseminoprotein). PSA and hK2, members of the kallikrein family, are elevated in sera of men with prostate cancer. In a comprehensive analysis that included sequencing of all coding, flanking, and 2 kb of putative promoter regions of all 15 kallikrein (KLK) genes spanning approximately 280 kb on chromosome 19q, we identified novel single-nucleotide polymorphisms (SNP) and genotyped 104 SNPs in 1,419 cancer cases and 736 controls in Cancer Prostate in Sweden 1, with independent replication in 1,267 cases and 901 controls in Cancer Prostate in Sweden 2. This verified prior associations of SNPs in KLK2 and in MSMB (but not in KLK3) with prostate cancer. Twelve SNPs in KLK2 and KLK3 were associated with levels of PSA forms or hK2 in plasma of control subjects. Based on our comprehensive approach, this is likely to represent all common KLK variants associated with these phenotypes. A T allele at rs198977 in KLK2 was associated with increased cancer risk and a striking decrease of hK2 levels in blood. We also found a strong interaction between rs198977 genotype and hK2 levels in blood in predicting cancer risk. Based on this strong association, we developed a model for predicting prostate cancer risk from standard biomarkers, rs198977 genotype, and rs198977 x hK2 interaction; this model had greater accuracy than did biomarkers alone (area under the receiver operating characteristic curve, 0.874 versus 0.866), providing proof in principle to clinical application for our findings.
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PMID:Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms: kallikreins and prostate cancer. 2042 35

The underlying mechanism of failed androgen ablation therapy is unknown. It is recognised that under therapeutic conditions the androgen receptor (AR) remains functionally active independent of hormone stimulation and may function through an alternative pathway. We report a novel cooperative interaction between CRKL (an intracellular signalling adaptor protein) and the AR. We demonstrate by biochemical and genetic approaches that CRKL is associated with the AR complex and is localised in the nucleus of prostate cancer cells and patient tissue biopsies. The interaction between CRKL and the AR is functionally relevant as demonstrated by its presence on the enhancer region of an androgen regulated gene (human Kallikrein-2), its upregulation of PSA, and reduction in AR transactivation following its disruption by siRNA knockdown. In the presence of the AR inhibitor casodex, the expression of CRKL co-stimulated by growth factors is able to rescue AR activity independent of hormone. Our data provides insight on how a non-nuclear factor such as CRKL may interact with the AR complex to bypass hormone dependency by using an alternative growth factor signalling pathway in advanced prostate cancer.
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PMID:Interaction between AR signalling and CRKL bypasses casodex inhibition in prostate cancer. 2068 58

Changes in proteolytic activity are associated with several diseases, including cancer. Proteases are potential drug targets and targeting of proteases is used for treatment of various conditions/diseases, like high blood pressure and HIV. We present here detailed protocols for basic evaluation of the effects of peptides on the activity of proteases, using kallikrein-related peptidases KLK2 and KLK3 (also known as hK2 and PSA), and trypsin as examples. KLK2 and KLK3 are major prostatic proteases, and they are potential targets for prostate cancer treatment. KLK2 has trypsin-like activity and KLK3 chymotrypsin-like activity. By phage display technology, we have developed peptides that specifically stimulate KLK3-activity and other peptides that inhibit KLK2 or trypsin. The effect of the peptides on the proteolytic activity of proteases can be studied using substrates, the cleavage of which generates detectable signal, allowing rapid evaluation of protease activity. The cleavage of protein substrates can be detected by SDS-PAGE, followed by staining of the proteins. We also describe graphical analysis of the IC50-value, the effect of a peptide on Michaelis-Menten constant (K(m)) and the maximal reaction rate (V(max)).
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PMID:Evaluation of peptides as protease inhibitors and stimulators. 2414 2

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.
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PMID:Proteolytic activity of prostate-specific antigen (PSA) towards protein substrates and effect of peptides stimulating PSA activity. 2523 4


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