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)

T3 plays an important role in the regulation of cell growth and differentiation. In this study, we show the interactive effects of T3 and androgens on the growth response and expression of the prostate-specific genes, PSA (prostate-specific antigen) and hK2 (human glandular kallikrein), in the human prostate cancer cell line, LNCaP. T3 alone showed pronounced growth enhancement in a dose-dependent fashion. However, in the presence of androgens, higher concentrations of T3 were required to produce additional proliferative effects. T3, androgens, or a combination of the two up-regulated PSA protein production in a dose-dependent fashion, but T3 had little stimulatory effect on hK2 protein expression, regardless of the presence or absence of androgens. Using gene transfer assays, T3 alone showed no effect on transcriptional activation of a reporter gene mediated by the PSA or hK2 enhancer/promoters. T3 potentiated the androgen-mediated transcription of the PSA gene but not that of the hK2 gene. A previous study suggested that the T3 effect on PSA protein expression was caused by an up-regulation of the androgen receptor (AR) protein by T3. Our results contradict these. Although AR expression was increased by T3 alone, Western blot analysis showed that the total cellular AR level was not further increased by T3 in the presence of androgens, in comparison with cells stimulated by androgens alone. Both Western blot analysis and a gel DNA band shift assay revealed that nuclear AR was not increased by T3. This study suggests that transcription factor(s) other than the AR may mediate T3 enhancement of androgenic induction of PSA expression.
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PMID:Interactive effects of triiodothyronine and androgens on prostate cell growth and gene expression. 1009 1

The morbidity and mortality associated with prostate cancer can almost universally be attributed to the consequences of metastases to the bone. While clinically there have been descriptive reports of these lesions and their detection by bone scan, there is an embrrassing paucity of reports as to the mechanisms of prostate cancer cell trafficking to the bone, adaptation to the bone environment, pertubation of the normal bone reformation process and the events leading to cachexia and death. In recent years, there have been numerous in vitro studies suggesting that PSA and hK2 may play a significant biological role in these events. Also, recent data generated form reverse transcription polymerase chain reaction assays reveal that metastasis to the bone may be an early event which further underscores the need to better understand this complex and critically important process. This commentary highlights several general concepts and a few specific issues related to CaP bone metastasis with the intent of revealing numerous opportunities for further investigation and inquiry.
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PMID:Mechanisms, hypotheses and questions regarding prostate cancer micrometastases to bone. 1045 76

Human kallikrein (hK) 2 is an arginine-selective serine protease expressed predominantly in the prostate that has an 80% sequence identity with prostate-specific antigen. Expression of hK2 is elevated in the tumor epithelium compared to benign prostate tissue. We have purified, sequenced, and identified a novel hK2 complex in prostate tissue consisting of hK2 and a serine protease inhibitor known as protease inhibitor-6 (PI-6). This 64-kDa SDS-PAGE stable complex is elevated in the tumor and is approximately 10% of total hK2. No comparable complex of prostate-specific antigen was detected. PI-6, also known as cytoplasmic antiprotease, has been characterized as an intracellular inhibitor of trypsin and chymotrypsin-like proteases, which has high homology to plasminogen activator inhibitor 1 and 2. The physiological role of PI-6 in the prostate and its relationship to hK2 and prostate cancer are under investigation.
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PMID:Identification of a novel complex between human kallikrein 2 and protease inhibitor-6 in prostate cancer tissue. 1046 85

In a search for prostate-specific genes in the human expressed sequence tag (EST) database, we identified a seemingly unique EST cluster C81. Experimental data linked C81 to the human hKLK2 gene that encodes a prostate specific serine protease-human glandular kallikrein (hK2). We uncovered a full-length hKLK2 cDNA corresponding to a 3.0 kb hKLK2 mRNA by PCR and sequence analysis. The 3.0 kb transcript accounts for about 25% of the hKLK2 transcripts as compared to the previously known 1.5 kb transcript. We also identified a third spliced form of the hKLK2 gene produced by alternative splicing between intron III and exon 4. This spliced form was detected in normal prostate, prostate cancer and the prostate adenocarcinoma cell line LNCaP. The identification of long hKLK2 transcript and an alternative spliced form of the hKLK2 gene indicates that regulation of the gene is complex.
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PMID:Identification of three new alternate human kallikrein 2 transcripts: evidence of long transcript and alternative splicing. 1054 17

Human glandular kallikrein 2 (hK2) is a serine protease expressed mainly by the prostate gland with 80% identity in primary structure to prostate specific antigen (PSA). hK2 has proven to be a useful marker of prostate cancer which can be used in combination with PSA to better discriminate between prostate cancer and benign prostate hyperplasia. The studies on hK2 have been hampered by its very low phyciological levels (6 microgram.mL-1), its close similarity to PSA, and the low expression levels obtained using recombinant procedures to produce hK2 (0.7 mg.L-1). We have now generated propeptide mutations of hK2 which can be used to isolate stable, inactive prohK2 mutants. Compared with wild-type hK2, expression of the propeptide hK2 mutants increases the expression levels up to 15-40-fold giving 10-30 mg hK2.L-1. These results indicate that the low expression levels of wild-type hK2 are related to the activation or autoactivation of the wild-type enzyme and the instability of the active protease in cell culture and possibly also in tissue. The purified mutant hK2 may be activated by either enterokinase or factor Xa to generate an enzyme for use in functional studies with the characteristics of the original wild-type protein. Further, the stable inactive mutant hK2 protein may be used for immunizations to generate novel monoclonal antibodies, used as standard material for clinical assays or in crystallization studies where large quantities of protein are required.
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PMID:Production and activation of recombinant hK2 with propeptide mutations resulting in high expression levels. 1058 1

Immunoassays for prostate-specific antigen (PSA) using monoclonal or polyclonal antibodies have clinical applications, such as monitoring and early detection of prostate cancer. However, PSA shares 80% sequence homology with human glandular kallikrein (hK2). In the present study, we have used SDS-PAGE and Western blotting of a recombinant form of hK2 to determine the degree of cross-reactivity in a panel of 83 antibodies submitted to the ISOBM TD-3 PSA Workshop. From this panel, 24 of the 83 antibodies showed cross-reactivity with hK2. The majority of these antibodies showed binding to conformationally independent or linear epitopes. Fourteen of these antibodies appear to map to the same epitope group, indicating the existence of a dominant and linear immunogenic domain shared by PSA and hK2.
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PMID:Western blotting analysis of antibodies to prostate-specific antigen: cross-reactivity with human kallikrein-2. 1062 12

The traditional human kallikrein gene family consists of three genes, namely KLK1 [encoding human kallikrein 1 (hK1) or pancreatic/renal kallikrein], KLK2 (encoding hK2, previously known as human glandular kallikrein 1) and KLK3 [encoding hK3 or prostate-specific antigen (PSA)]. KLK2 and KLK3 have important applications in prostate cancer diagnostics and, more recently, in breast cancer diagnostics. During the past two to three years, new putative members of the human kallikrein gene family have been identified, including the PRSSL1 gene [encoding normal epithelial cell-specific 1 gene (NES1)], the gene encoding zyme/protease M/neurosin, the gene encoding prostase/KLK-L1, and the genes encoding neuropsin, stratum corneum chymotryptic enzyme and trypsin-like serine protease. Another five putative kallikrein genes, provisionally named KLK-L2, KLK-L3, KLK-L4, KLK-L5 and KLK-L6, have also been identified. Many of the newly identified kallikrein-like genes are regulated by steroid hormones, and a few kallikreins (NES1, protease M, PSA) are known to be downregulated in breast and possibly other cancers. NES1 appears to be a novel breast cancer tumor suppressor protein and PSA a potent inhibitor of angiogenesis. This brief review summarizes recent developments and possible applications of the newly defined and expanded human kallikrein gene locus.
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PMID:The new human kallikrein gene family: implications in carcinogenesis. 1067 91

Androgens via their cognate receptor may be involved in the development and progression of prostate cancer. The aim of this study was to determine whether tea polyphenols have inhibitory effects on androgen action in an androgen-responsive, prostate cancer cell line, LNCaP. The tea polyphenol, EGCG, inhibited LNCaP cell growth and the expression of androgen regulated PSA and hK2 genes. Moreover, EGCG had a significant inhibitory effect on the androgenic inducibility of the PSA promoter. Immunoblotting detected a decrease in androgen receptor protein with treatments of the tea polyphenols EGCG, GCG and theaflavins. Northern blot analysis showed decreased levels of androgen receptor mRNA by EGCG. Transient transfections demonstrated that EGCG and theaflavins could repress the transcriptional activities of the androgen receptor promoter region. An Sp1 binding site in the androgen receptor gene promoter is an important regulatory component for its expression. This study suggests Sp1 is the target for the tea polyphenols because treatments of EGCG decreased the expression, DNA binding activity and transactivation activity of Sp1 protein. In conclusion, we have described a new property of tea polyphenols that inhibits androgen action by repressing the transcription of the androgen receptor gene.
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PMID:Tea polyphenols down-regulate the expression of the androgen receptor in LNCaP prostate cancer cells. 1077 82

The serine proteinase prostate-specific antigen (PSA), and its complex with the serine proteinase inhibitor alpha(1)-antichymotrypsin (ACT), have been used as markers for the diagnosis of prostate cancer. PSA prepared from seminal fluid is typically contaminated with the trypsin-like glandular kallikrein (hK2). Here we describe a convenient and reproducible preparation of catalytically active recombinant PSA (rPSA) and demonstrate an overall similarity in the properties of cloned and refolded rPSA to PSA purified from seminal fluid. We also present results that are relevant for increasing the sensitivity of assays of PSA activity in biological fluids, for the putative role of PSA activity in physiologically important processes, including prostate cancer metastasis, and for the design of PSA inhibitors. Specifically, we find that added salts, in particular NaCl, give rise to dramatic increases in rPSA catalytic activity, as does added glycerol. On the other hand, Zn(2+), spermine, and spermidine, each a major component of seminal and prostatic fluid, strongly inhibit rPSA activity, with Zn(2+) being a non-competitive inhibitor while spermine is a competitive inhibitor. Citrate, also a major component of seminal and prostatic fluid, spermine, and spermidine each protect rPSA from Zn(2+) inhibition, presumably via Zn(2+) sequestration. Finally, rPSA efficiently proteolyzes several protein substrates.
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PMID:The preparation and catalytic properties of recombinant human prostate-specific antigen (rPSA). 1096 94

Human glandular kallikrein (hK2) is an androgen regulated protein primarily expressed in the prostate and recently identified as a novel prostate cancer marker. A 5 kb 5' flanking region of the hK2 gene was isolated and sequenced to characterize the regulatory mechanisms for the expression of hK2 in the androgen responsive prostate cell line, LNCaP. Using gene transfer, gel shift, and mutagenesis assays we have identified an ARE in the 5' far upstream promoter region of the hK2 gene that is crucial for its regulation in LNCaP cells. This study further demonstrated that the hK2 upstream ARE plays a predominant role in androgenic response. More interestingly, previously identified AREs in the prostate specific antigen promoter and the hK2 proximal promoter exert little activity in LNCaP cells. This study for the first time identifies a unique ARE that alone mediates the function of the androgen receptor in LNCaP cells in a cell dependent manner. This study also examines the activity of this ARE with 1alpha, 25 dihydroxy-vitamin D3 on the expression of the hK2 gene in LNCaP cells.
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PMID:An androgen response element mediates LNCaP cell dependent androgen induction of the hK2 gene. 1106 55


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