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)

The glutathione S-transferases (GSTs) are involved in the metabolism of numerous potential prostate carcinogens. Common homozygous germ-line deletions exist in the genes that encode GST-mu (GSTM1) and GST-theta (GSTT1) and preclude enzyme expression. To evaluate whether GSTM1 and/or GSTT1 contribute to prostate cancer (CaP) etiology, we studied 237 incident CaP cases and 239 age- and race-matched controls. The probability of having CaP was increased in men who had nondeleted (functional) genotypes at GSTT1 (odds ratio, 1.83; 95% confidence interval, 1.19-2.80) but not GSTM1 (odds ratio, 1.07; 95% confidence interval, 0.74-1.55). No interaction of these genes in CaP etiology was observed. GST-theta is highly expressed in the prostate and can produce genotoxic effects upon exposure to specific carcinogens. These results suggest that GSTT1 is associated with CaP risk.
 ...
PMID:Glutathione S-transferase-mu (GSTM1) and -theta (GSTT1) genotypes in the etiology of prostate cancer. 1020 29

Prostate secretory protein (PSP94, 94 amino acids) is one of the most abundant proteins secreted from the prostate. Its biological role is unknown and still controversial, although it is assumed to have the potential to be a biomarker and a suppressor of prostate cancer. In order to establish an animal model to further elucidate its biological role, we expressed the mature form of rat PSP94 in Escherichia coli, using a glutathione S-transferase (GST) fusion expression vector; we generated a polyclonal rabbit antibody against the recombinant protein. The antibody specifically recognized recombinant rat PSP94 and cross-reacted only very weakly with its human homologue. Using the characterized anti-rat PSP94 antibody, we found that PSP94 was located primarily in rat prostate. Furthermore, PSP94 is present at different levels in different lobes of rat prostate, with significant levels detectable only in the lateral lobe (LP). In addition, the most abundant PSP94 expression was found in the prostate lobe secretions, and PSP94 levels in LP secretions were at least seven times higher than in secretions from the dorsal prostate (DP). The rat ventral prostate (VP) and other regions of the male accessory glands were found to be almost completely devoid of PSP94. Since most rat prostate dysplasia induced by steroid hormone treatment occurs only in dorsolateral prostate, prostate tissue-specific expression and the expression of PSP94 in dorsolateral, but not other, lobes of the prostate suggest a potential role in prostate targeting and prostate cancer development.
 ...
PMID:Differential expression of PSP94 in rat prostate lobes as demonstrated by an antibody against recombinant GST-PSP94. 1041 42

Epigenetic mechanisms may be the main driving force for critical changes in gene expression that are responsible for progression of prostate cancers. The three most extensively characterized mechanisms for epigenetic gene-regulation are (i) changing patterns of DNA methylation, (ii) histone acetylations/deacetylations, and (iii) alterations in regulatory feedback loops for growth factors. Several studies have indicated that DNA hypermethylation is an important mechanism in prostate cancer for inactivation of key regulatory genes such as E-cadherin, pi-class glutathione S-transferase, the tumor suppressors CDKN2 and PTEN, and IGF-II. Similarly, histone acetylations and deacetylations are frequently associated respectively with transcriptional activation (e.g. IGFBP-2 and p21) and repression (e.g. Mad:Max dimers) of genes linked to prostate cancer progression. Recently, histone acetyltransferase and deacetylase activities have been shown to be intrinsic with transcriptional coregulator proteins that bind to steroid receptors (e.g. SRC-1 and PCAF). Changes in regulatory feedback loops for growth factors with prostate cancer progression tend toward shifts from paracrine to autocrine control where the receptor and ligand are produced by the same cell. While there are several examples of this progression pattern in prostate tumors such as with IGF, FGF, TGF-alpha and their respective receptors, the precise mechanism (i.e. epigenetic or mutational) is less certain. In the context of treatment options, the contribution of mutational versus epigenetic events to prostate cancer progression is an important consideration. Irreversible genetic changes are likely to be less amenable to therapeutic control than are epigenetic ones.
 ...
PMID:Epigenetic mechanisms for progression of prostate cancer. 1045 84

The development of prostate cancer is dependent on heredity, androgenic influences, and exposure to environmental agents. A high intake of dietary fat is associated with an increased risk of prostate cancer, either through influence on steroid hormone profiles or through production of carcinogenic compounds that require biotransformation by enzymes. The polymorphic glutathione S-transferase (GST), N-acetyltransferase (NAT), and cytochrome P450 (CYP) enzymes are of particular interest in prostate cancer susceptibility because of their ability to metabolize both endogenous and exogenous compounds, including dietary constituents. Association between different NAT2, CYP2D6, CYP2C19 and GSTP1 genotypes and prostate cancer was studied in a Swedish and Danish case-control study comprising 850 individuals. The combined Swedish and Danish study population was analysed by polymerase chain reaction for the NAT2 alleles *4, *5A, *5B, *5C, *6 and *7, and for the CYP2D6 alleles *l, *3 and *4. The Swedish subjects were also analysed for the CYP2C19 alleles *1 and *2, and the GSTP1 alleles *A, *B and *C. No association was found between prostate cancer and polymorphisms in NAT2, CYP2D6, CYP2C19 or GSTP1. An association between CYP2D6 poor metabolism and prostate cancer was seen among smoking Danes; odds ratio 3.10 (95% confidence interval 1.07; 8.93), P = 0.03, but not among smoking Swedes; odds ratio 1.19 (95% confidence interval 0.41; 3.42), P = 0.75. Smoking is not a known risk factor for prostate cancer, and the association between CYP2D6 poor metabolism and prostate cancer in Danish smokers may have arisen by chance.
 ...
PMID:Polymorphisms in NAT2, CYP2D6, CYP2C19 and GSTP1 and their association with prostate cancer. 1047 Oct 65

The tumor suppressor gene PTEN/MMAC-1/TEP-1 (referred to hereafter as PTEN) maps to chromosome 10q23 and encodes a dual specificity phosphatase. The PTEN protein negatively regulates cell migration and cell survival and induces a G1 cell cycle block via negative regulation of the phosphatidylinositol 3'-kinase/protein kinase B/Akt signaling pathway. PTEN is frequently mutated or deleted in both prostate cancer cell lines and primary prostate cancers. A murine polyclonal antiserum was raised against a glutathione S-transferase fusion polypeptide of the COOH terninus of PTEN. Archival paraffin tissue sections from 109 cases of resected prostate cancer were immunostained with the antiserum, using DU145 and PC-3 cells as positive and negative controls, respectively. PTEN expression was seen in the secretory cells. Cases were considered positive when granular cytoplasmic staining was seen in all tumor cells, mixed when areas of both positive and negative tumor cell clones were seen, and negative when adjacent benign prostate tissue but not tumor tissue showed positive staining. Seventeen cases (15.6%) of prostate cancer were positive, 70 cases (64.2%) were mixed, and 22 cases (20.2%) were negative. Total absence of PTEN expression correlated with the Gleason score (P = 0.0081) and correlated more significantly with a Gleason score of 7 or higher (P = 0.0004) and with advanced pathological stage (American Joint Committee on Cancer stages T3b and T4; P = 0.0078). Thus, loss of PTEN protein is correlated with pathological markers of poor prognosis in prostate cancer.
 ...
PMID:Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. 1048 74

What defines the boundaries between methylated and unmethylated domains in the genome is unclear. In this study we used bisulfite genomic sequencing to map the boundaries of methylation that flank the 5'- and 3'-ends of the CpG island spanning the promoter region of the glutathione S-transferase (GSTP1) gene. We show that GSTP1 is expressed in a wide range of tissues including brain, lung, skeletal muscle, spleen, pancreas, bone marrow, prostate, heart, and blood and that this expression is associated with the CpG island being unmethylated. In these normal tissues a marked boundary was found to separate the methylated and unmethylated regions of the gene at the 5'-flank of the CpG island, and this boundary correlated with an (ATAAA)(19-24) repeated sequence. In contrast, the 3'-end of the CpG island was not marked by a sharp transition in methylation but by a gradual change in methylation density over about 500 base pairs. In normal tissue the sequences on either side of the 5'-boundary appear to lie in separate domains in which CpG methylation is independently controlled. These separate methylation domains are lost in all prostate cancer where GSTP1 expression is silenced and methylation extends throughout the island and spans across both the 5'- and 3'-boundary regions.
 ...
PMID:A distinct sequence (ATAAA)n separates methylated and unmethylated domains at the 5'-end of the GSTP1 CpG island. 1077 22

New diagnostic tools are needed for the early detection of prostatic cancer. The molecular detection of prostate cancer cells in ejaculates was evaluated using complementary PCR-based methods. LNCaP cells, a cell line derived from prostatic carcinoma, were spiked into normal seminal ejaculates and the prostatic epithelial component of the specimens was isolated by immunomagnetic bead sorting, using a monoclonal antibody to prostate-specific membrane antigen (PSMA). Ejaculates from nine patients with a recent diagnosis of prostate cancer were processed in a similar fashion, using LNCaP-spiked aliquots as an internal positive control. Telomerase expression was evaluated by the telomeric repeat amplification protocol (TRAP) and glutathione S-transferase gene promoter (GSTP1) hypermethylation was evaluated by methylation-sensitive restriction endonuclease digestion and PCR amplification. Telomerase activity was detected in LNCaP cells recovered from normal seminal ejaculates but was not found in all nine samples from patients with prostate cancer. The sensitivity of GSTP1 analysis was similar to telomerase analysis for the detection of LNCaP cells from normal ejaculate samples but was positive in ejaculates from four out of nine patients with prostate cancer. GSTP1 DNA methylation status is more sensitive than telomerase analysis for the detection of malignant cells in seminal ejaculates from patients with prostate cancer.
 ...
PMID:Comparison of telomerase activity and GSTP1 promoter methylation in ejaculate as potential screening tests for prostate cancer. 1097 Jul 25

Prostate-specific antigen (PSA) is a serine protease with highly prostate-specific expression. Measurement of PSA in serum is widely used for diagnosis and monitoring of prostate cancer. PSA dissolves the seminal gel forming after ejaculation. It has been suggested to mediate invasion and metastasis of prostate cancer but also to exert antiangiogenic activity. We have identified peptides specific for PSA by screening cyclic phage display peptide libraries. PSA-binding peptides were isolated from four different libraries and produced as a fusion protein with glutathione S-transferase (GST). The phage and fusion proteins were shown to bind to PSA specifically as indicated by lack of binding to other serine proteinases. A peptide with four cysteines showed the highest affinity for PSA. Zn2+, an inhibitor of PSA activity, increased the affinity of the peptides to PSA. The binding specificity was characterized by cross-inhibition using monoclonal anti-PSA antibodies of known epitope specificities. The peptides bound to the same region as mAbs specific for free PSA indicating that they bind close to the active site of the enzyme. The peptides enhanced the enzyme activity of PSA against a chromogenic substrate. These results show that peptides binding to PSA and modulating its enzyme activity can be developed by phage display technique. The peptides have the potential to be used for identification of PSA variants and for imaging and targeting of prostatic tumors.
 ...
PMID:Identification of novel prostate-specific antigen-binding peptides modulating its enzyme activity. 1101 75

Promoter hypermethylation of the glutathione S-transferase P1 gene (GSTP1) is the most frequent DNA alteration in prostatic carcinoma. Because this epigenetic DNA alteration can be reliably detected by methylation-specific PCR (MSP), we applied this new technique for molecular detection of prostate cancer in various human bodily fluids. We investigated GSTP1 promoter hypermethylation in DNA isolated from plasma, serum, ejaculate, and urine after prostate massage and from prostate carcinoma tissues from 33 patients with prostate cancer and 26 control patients with benign prostatic hyperplasia (BPH). Fluorescently labeled MSP products were analyzed on an automated gene sequencer. Whereas GSTP1 promoter hypermethylation was not detectable by MSP in prostate tissue and bodily fluids from patients with BPH, we found it in 94% of tumors (16 of 17), 72% of plasma or serum samples (23 of 32), 50% of ejaculate (4 of 8) and 36% of urine (4 of 11) from patients with prostate cancer. Additionally, MSP identified circulating tumor cells in 30% (10 of 33) of prostate cancer patients. Analysis of GSTP1 promoter hypermethylation by MSP thus provides a specific tool for molecular diagnosis of prostate cancer in bodily fluids.
 ...
PMID:Fluorescent methylation-specific polymerase chain reaction for DNA-based detection of prostate cancer in bodily fluids. 1108 8

It has been reported that individuals who express GSTT1, the gene coding for the theta class of the glutathione S-transferases (GSTs), have an elevated risk of prostate cancer (CaP). This result is supported by studies that show glutathione conjugation of some xenobiotics by the GSTs can produce mutagenic intermediates. However, the potential role of environmental factors in modifying the risk of CaP conferred by GSTT1 is not known. We investigated whether there was an interaction between smoking and the non-deleted genotypes of the mu (GSTM1) and theta (GSTT1) GST genes using a clinic-based study of 276 CaP cases and 499 controls. We observed no main effect of smoking (odds ratio, 0.95; confidence interval, 0.69-1.29) or GSTM1 (odds ratio, 1.00; confidence interval, 0.73-1.36) with CaP, but did observe a statistically significant main effect of GSTT1 with CaP (odds ratio, 1.61; confidence interval, 1.14-2.28) as reported previously. No interaction between smoking and GSTM1 was observed. A significant increase in the probability of having CaP was observed in men who were both smokers and carried a non-deleted GSTT1 genotype compared with men who had neither or only one of these risk factors (P = 0.049). Approximately 30.9% of CaP cases in this study could be attributed to the smoking x GSTT1 interaction. Whereas the mechanism of this interaction is not known, it is plausible that the metabolism of carcinogenic intermediates or the response to chronic inflammation associated with smoking may be modulated by the GSTT1 genotype and may modify CaP risk.
 ...
PMID:The glutathione S-transferase-mu and -theta genotypes in the etiology of prostate cancer: genotype-environment interactions with smoking. 1114 18


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>