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)

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and related compounds modulate various endocrine functions by enhancing ligand metabolism, altering hormone synthesis, down regulating receptor levels, and interfering with gene transcription. In the present study, we investigated the effects of TCDD on testosterone signal transduction pathways and vice versa in the androgen receptor (AR) positive LNCaP prostate cancer cell line. TCDD induced CYP1A1 mRNA and related enzyme activity in these cells, with dose and time-dependence. Both normal and testosterone-stimulated cell growth was inhibited by TCDD. The expression levels of the aryl hydrocarbon receptor (AhR), the aryl hydrocarbon receptor nuclear translocator (ARNT), and AR were not affected by exposure to TCDD at a dose of 10 nM for a 24 hr time period. Testosterone treatment dose-dependently inhibited the TCDD-induced CYP1A1 mRNA accumulation and related enzyme activity. Reciprocally, TCDD also dose-dependently inhibited testosterone-dependent transcriptional activity and testosterone-regulated prostate specific antigen (PSA) expression. Taken together, these results demonstrate antiandrogenic functions of TCDD and a specific ligand-induced bilateral transcriptional interference between TCDD and testosterone mediated signal transduction pathways.
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PMID:Cross-talk between 2,3,7,8-tetrachlorodibenzo-p-dioxin and testosterone signal transduction pathways in LNCaP prostate cancer cells. 1008 Sep 20

Epidemiological evidence suggests a link between meat consumption and prostate cancer. In this study, benign prostatic hyperplasia tissues, obtained by transurethral resection or radical retropubic prostatectomy from UK-resident individuals (n = 18), were examined for CYP1 expression and for their ability, in short-term organ culture, to metabolically activate carcinogens found in cooked meat. Semi-quantitative RT-PCR analysis of CYP1 expression detected CYP1A2 mRNA transcripts in the prostates of four individuals, as well as mRNA transcripts from CYP1A1 and CYP1B1. The compounds tested for metabolic activation were 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP; 500 microM, n = 9) and its metabolite N:-hydroxy PhIP (20 microM, n = 8), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ; 500 microM, n = 6) and benzo[a]pyrene (B[a]P; 50 microM, n = 5). After incubation (PFMR medium, 22 h, 37 degrees C), DNA was isolated from tissue fragments and DNA adducts were detected and quantified by (32)P-postlabelling analysis. DNA adduct formation was detected in all samples incubated with PhIP (mean, adducts per 10(8) nucleotides), N:-hydroxy-PhIP (2736/10(8)) or B[a]P (1/10(8)). IQ-DNA adducts were detected in 5/6 tissues (mean, 1/10(8)). The CYP1 inhibitor alpha-naphthoflavone (10 microM) reduced B[a]P-DNA adduct formation in tissues from two individuals by 96 and 64%, respectively. This pilot study shows that human prostate tissue can metabolically activate 'cooked meat' carcinogens, a process that could contribute to prostate cancer development.
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PMID:Metabolic activation of carcinogens and expression of various cytochromes P450 in human prostate tissue. 1096

Associations between genetic polymorphisms of CYP1A1, CYP1A2, CYP2E1, GSTM1 and GSTT1 and prostate cancer (PCa) were analyzed in a case-control study of 315 individuals. The frequency of valine (Val)/valine (Val) genotypes for CYP1A1 was 11.3% in cases compared with 5.5% in controls, this polymorphism thus being associated with a significantly increased risk of PCa (odds ratio=2.4, 95% confidence interval (CI)=1.01-5.57). No links were detected between PCa and polymorphisms in other enzymes. However, the combination of CYP1A1 (Ile/Val and/or Val/Val) polymorphisms with the GSTM1 null type resulted in an OR of 2.2 (CI=1.10-4.57, 1.12-4.20, respectively). This study suggests that the CYP1A1 polymorphism and its combination with GSTM1 may be associated with PCa susceptibility in the Japanese population.
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PMID:Genetic polymorphisms in cytochrome P450 (CYP) 1A1, CYP1A2, CYP2E1, glutathione S-transferase (GST) M1 and GSTT1 and susceptibility to prostate cancer in the Japanese population. 1127 66

The study was conducted to investigate whether 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces cytochrome P450 (CYP) 1A1 and CYP1B1 via the aryl hydrocarbon receptor (AhR) in the hormone-independent human prostate cancer cell lines PC 3 and DU 145. No quantitative differences in the expression of AhR and its partner transcription factor ARNT were seen in low and high passage number PC 3 and DU 145 cells in the absence and presence of TCDD as assessed by RT-PCR and Western blotting. However, CYP1A1/1B1 activity, measured by the 7-ethoxyresorufin-O-deethylase (EROD) assay, was induced by 10 and 100 nM TCDD only in high passage number PC 3 and DU 145 cells (PC 3, 7.7- and 2-fold stimulation; DU 145, 8.5- and 19.7-fold stimulation). Besides stimulation of EROD activity, induction of the expression of CYP1A1 and, to a lesser extend, of CYP1B1 by TCDD was also demonstrated by RT-PCR and Western blotting. However, 1-100 nM TCDD did not significantly alter cell cycle distribution and cell growth for up to five days. The induction of CYP1A1 and CYP1B1 by TCCD in the hormone-independent prostate cancer cell lines suggests that CYP induction should be considered in patients with advanced prostate cancer. This could result in higher elimination rates of concomitant drugs metabolized by these particular CYP isoenzymes.
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PMID:The environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin induces cytochrome P450 activity in high passage PC 3 and DU 145 human prostate cancer cell lines. 1189 38

Association between genetic polymorphisms of CYP1A1 and familial prostate cancer risk was examined by a case-control study of 185 individuals. Although the individual analysis of m1 or m2 genotype of CYP1A1 showed no significant association with prostate cancer risk, the presence of any mutated alleles significantly increased prostate cancer risk in comparison with wild-type genotypes by combination analysis (odds ratio [OR]=2.38; 95% confidence interval [CI]=1.72-3.29; P=0.0069). Furthermore, metastatic cancer had a significant association with mutated alleles of m1 and m2. These finding suggested that CYP1A1 polymorphisms has an association with prostate cancer risk, especially with progression of prostate cancer.
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PMID:Association of the genetic polymorphism in cytochrome P450 (CYP) 1A1 with risk of familial prostate cancer in a Japanese population: a case-control study. 1276 26

Constitutive and benzo[a]pyrene (B[a]P) inducible expression of CYP1A1 and CYP1A2 in prostate cancer and normal prostate epithelial cells were examined by immunoblotting. Androgen independent prostate cancer cell lines DU145 and PC3 have constitutive expression of CYP1A and CYP1A1 and CYP1A2, respectively. Four micromolar B[a]P did not appear to induce CYP1A1 or CYP1A2 expression in DU145 or PC3 cells. The androgen dependent prostate cancer cell line, LnCap, also has constitutive expression of CYP1A1 and CYP1A2. However, both CYP1A1 and CYP1A2 are induced by treatment of LnCap cells with 4 microM B[a]P. Untreated normal prostate and primary prostate tumor cells have no detectable CYP1A1 expression. Treatment with 4 microM B[a]P induced CYP1A1 expression in both normal and primary tumor prostate cells. Constitutive CYP1A2 expression was detected in normal prostate cells with little or no induction by exposure to 4 microM B[a]P. Primary prostate tumor cells did not show constitutive expression of CYP1A2. However, CYP1A2 was induced by 4 microM B[a]P in primary prostate tumor cells. These observations indicate that hormonal and cancer specific factors affect the expression and induction of the phase I metabolic enzymes, CYP1A1 and CYP1A2 in prostate cells. These observations may be related to the potential smoking-linked higher risk of prostate cancer development and morbidity of prostate cancer patients who smoke.
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PMID:Constitutive and inducible expression of cytochromes P4501A (CYP1A1 and CYP1A2) in normal prostate and prostate cancer cells. 1474

LNCaP prostate cancer cells express the aryl hydrocarbon receptor (AhR), and treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1A1 protein and an Ah-responsive reporter gene. Similar results were obtained with the selective AhR modulator 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF); however, TCDD but not 6-MCDF induced degradation of the AhR protein. TCDD and 6-MCDF inhibited growth of LNCaP cells, and inhibitory AhR-androgen receptor (AR) crosstalk was investigated in cells transfected with constructs containing the androgen-responsive probasin promoter (-288 to +28) (pPB) or three copies of the -244 to -96 region of this promoter (pARR(3)). Ten nanomolar dihydrotestosterone (DHT) and 17 beta-estradiol (E2) induced transactivation in LNCaP cells transfected with pPB or pARR(3); however, inhibitory AhR-AR crosstalk was observed only with the latter construct. 6-MCDF and TCDD did not inhibit DHT- or E2-induced transactivation in ZR-75 human breast cancer cells, indicating that these interactions were promoter and cell context-dependent. Both E2 and DHT stabilized AR protein in LNCaP cells; however, cotreatment with TCDD or 6-MCDF decreased AR protein levels. These results indicate that inhibitory AhR-AR crosstalk in prostate cancer cells is complex and for some responses, AR protein stability may play a role.
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PMID:Aryl hydrocarbon receptor-mediated inhibition of LNCaP prostate cancer cell growth and hormone-induced transactivation. 1502 81

Glutathione S-transferase P1 (GSTP1) is markedly downregulated in prostate cancer and prostatic intraepithelial neoplasia compared to normal prostate tissue. Downregulation of GSTP1 may, therefore, be an early event in prostate carcinogenesis. An A-->G polymorphism at nucleotide 313 results in an amino acid substitution (Ile105Val) in the substrate binding site of GSTP1 and reduces catalytic activity of GSTP1. In a study of 36 prostate cancer patients, Harries et al. reported that the Ile/Ile genotype is associated with a decreased risk of prostate cancer (odds ratio 0.4 (0.17-0.82)). We sought to confirm this finding and to examine the impact of this polymorphism together with several related polymorphisms implicated as risk factors for carcinogen-associated malignancies. One hundred and seventeen patients with prostate adenocarcinoma and 183 population-based controls were recruited to this case-control study. Genotyping of the GSTP1 (Ile105Val), GSTM1 (null), GSTT1 (null) and CYP1A1 (Ile462Val) genes was performed using polymerase chain reaction (PCR) based techniques on DNA prepared from peripheral blood. A questionnaire was used to collect demographic information from each subject. Cases were significantly older (P<0.0001) and had significantly greater family history of prostate cancer (P<0.0001), confirming known risk factors for this disease. By chi(2) analysis, none of the genotype distributions varied among cases and controls. Using a logistic regression model to control for known risk factors we were also unable to demonstrate a significant association with prostate cancer for any of the polymorphisms tested. This population fails to identify a relationship between the above polymorphisms and prostate adenocarcinoma.
Prostate Cancer Prostatic Dis 2002
PMID:Polymorphisms of GSTP1 and related genes and prostate cancer risk. 1519 26

Prostate cancer (CaP) mostly occurs in the peripheral zone whereas benign prostatic hypertrophy (BPH) occurs in the transition zone. Human prostates (n = 12) were obtained, with ethical approval, from radical retropubic prostatectomies. Following resection, tissue sets consisting of peripheral zone and transition zone were isolated from a lobe pre-operatively identified as negative for CaP. Real-time RT-PCR was employed to quantitatively examine CYP1A1, CYP1A2 and CYP1B1. Quantifiable CYP1A1 expression was observed (in nine out of twelve tissue sets) whilst CYP1A2 mRNA transcripts, although detectable (in six out of twelve tissue sets), were unquantifiable. In ten tissue sets, 2- to 6-fold higher CYP1B1 expression in peripheral zone as compared to transition zone was observed. In the other two, equal CYP1B1 expression levels were observed; retrospective examination identified malignancy in one of the zones. Inter-individual variations (up to 10-fold) in CYP1B1 were also noted. Immunohistochemistry for CYP1B1 showed epithelial and stromal nuclear staining. Since CYP1B1 metabolises hormones and carcinogens our results, if confirmed, suggest that this enzyme may influence susceptibility to CaP.
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PMID:CYP1B1 expression in prostate is higher in the peripheral than in the transition zone. 1537 34

Despite high incidence rates of prostate cancer, the genetic basis of this disease is not well understood. An association between risk and the CYP1A1 polymorphism has been noticed for several cancers, and the GSTM1 gene is one of the most extensively studied genes concerning polymorphism and cancer risk. These gene polymorphisms may play a role in the development prostate cancer (PCa) in Turkish populations; we therefore assessed the association of CYP1A1 and GSTM1 polymorphisms in patients with PCa in our population through a case-control study. One hundred patients with PCa and 107 control subjects were analyzed with an allele-specific polymerase chain reaction method. No statistical differences in the distribution of the CYP1A1 Ile/Val genotype among PCa individuals were observed (OR = 1.076, 95% CI = 0.605-1.913). The patients with CYP1A1 Val/Val revealed a 2.8-fold higher risk of having prostate cancer than those with the wild-type Ile/Ile (OR = 2.846, 95% CI = 1.004-8.064). In other words, the presence of the Val/Val genotype significantly increased the risk of prostate cancer. The GSTM1 null genotype was found in 13.1% of the control subjects; no statistical differences were noted in the frequency of the null genotype in patients with PCa (OR = 1.558, 95% CI = 0.735-3.305). We also analyzed the effects of the CYP1A1 and GSTM1 genotypes in combination; however, no significant difference between cases and controls was observed in our study population. These data suggest that the CYP1A1 gene polymorphism may be associated with PCa susceptibility in Turkish men and that further studies will be needed to clarify the role of such variations in determining susceptibility to PCa.
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PMID:CYP1A1 and GSTM1 polymorphic genotypes in patients with prostate cancer in a Turkish population. 1538 79


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