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)

In the prostate, the enzyme encoded by the SRD5A2 gene (5alpha-reductase) converts testosterone to dihydrotestosterone, a potent androgen that has been hypothesized to play a role in the genesis of prostate cancer. Several polymorphisms have been identified in the SRD5A2 gene, including a valine-to-leucine substitution (V89L) at codon 89, a variable number of TA dinucleotide repeats and a missense substitution at codon 49 resulting in an amino acid substitution of alanine with threonine (A49T). To investigate the influence of these polymorphisms on prostate cancer risk, we conducted a case-control study nested within the Beta-Carotene and Retinol Efficacy Trial. Genotypes were determined by PCR-based capillary electrophoresis using genomic DNA isolated from 300 cases and 300 controls matched on the basis of race, age at enrollment (within 5 years), enrollment study center and year of randomization. There was no association between V89L genotypes and prostate cancer risk. The age- and race-adjusted odds ratio (OR) associated with the VL and LL genotypes were 1.06 (95% confidence interval (CI) = 0.75-1.49) and 0.99 (95% CI = 0.57-1.73), respectively, as compared to the VV genotype. The age- and race-adjusted odds ratio for men having 1 TA(9) or TA(18) allele was 0.98 (95% CI = 0.64-1.48) when compared to men without TA repeats. The corresponding odds ratio for men without the TA(0) alleles was 0.68 (95% CI = 0.21-2.19). The age- and race-adjusted odds ratio associated with having at least 1 T allele at codon 49 was 1.11 (95% CI = 0.58-2.11), as compared to the AA genotype. Our results do not support the hypothesis that the V89L and A49T polymorphisms in the SRD5A2 gene are related to the risk of prostate cancer, but are compatible with the suggestion from earlier studies that men who are homozygous for the TA(9) or (18) alleles and men who have the TA(9)/TA(18) genotype are at a modestly reduced risk.
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PMID:Polymorphic markers in the 5alpha-reductase type II gene and the incidence of prostate cancer. 1271 37

Several polymorphisms in the 5alpha-reductase type 2 (SRD5A2) gene have been implicated as risk factors for prostate cancer. We performed a meta-analysis of 9 studies (12 comparisons) with V89L genotyping (2558 prostate cancer cases and 3349 controls), 7 studies (8 comparisons) with A49T genotyping (1594 cases and 2137 controls), and 4 studies with TA repeat genotyping (1109 cases and 1378 controls). The random effects odds ratio (OR) for the L versus V allele was 1.02 [95% confidence interval (CI), 0.94-1.11]. There was no suggestion of an overall effect either in recessive or dominant modeling, and comparison of L/L versus V/V also showed no differential prostate cancer susceptibility (OR, 1.03; 95% CI, 0.83-1.28). The random effects OR for the T versus A allele was 1.56 (95% CI, 0.93-2.62). However, excluding the first published study there was no evidence for any effect (OR, 1.08; 95% CI, 0.72-1.61). Moreover, the T allele had a low prevalence (0%, 1%, and 2% in Asian, African and European controls, respectively). The random effects OR for longer versus short TA alleles was 0.88 (95% CI, 0.74-1.05). Longer TA allele homozygotes were nonsignificantly under-represented among prostate cancer cases (OR, 0.53; 95% CI, 0.26-1.06). We exclude a role for the V89L polymorphism in conferring susceptibility to prostate cancer. The A49T and TA repeat polymorphisms may have a modest effect on prostate cancer susceptibility, but bias and chance findings cannot be excluded; any genuine genetic effects would account only for a small proportion of prostate cancer in the population.
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PMID:SRD5A2 gene polymorphisms and the risk of prostate cancer: a meta-analysis. 1286

Prostate cancer is a leading cause of cancer death in American males. Androgens play an essential role in prostate development, growth and pathogenesis of benign prostate hyperplasia, and prostate cancer. Although testosterone is the main androgen secreted from the testes, dihydrotestosterone (DHT), a more potent androgen converted from testosterone by 5alpha-reductase isozymes, type 1 and 2, is the major androgen in the prostate cells. Thus, 5alpha-reductase(s) are critical in determining androgen activity in the prostate. However, it is unclear in prostate tumor cells whether 1 or 2 5alpha-reductase isozymes are expressed and whether they are functionally important. In the present report, we studied the importance of 5alpha-reductase isozymes in the androgen induction of prostate-specific antigen (PSA) gene expression in LNCaP prostatic tumor cells. Treatment with either testosterone or DHT in LNCaP cells produced dose- and time-dependent increases in PSA levels in the cell media and in PSA messenger RNA (mRNA) levels in the cells. However, testosterone-induced but not DHT-induced PSA gene expression was significantly inhibited by finasteride, a 5alpha-reductase inhibitor, in a dose-dependent manner. Furthermore, we demonstrated for the first time that both 5alpha-reductase-1 and 5alpha-reductase-2 mRNAs were expressed in LNCaP cells using reverse transcriptase-polymerase chain reaction (RT-PCR) and RT-PCR Southern blot analysis. These results suggest that both 5alpha-reductase isozymes are present and functionally important in prostatic tumor LNCaP cells and that DHT is a major mediator of androgen induction of PSA gene expression in these cells.
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PMID:Androgen-induced prostate-specific antigen gene expression is mediated via dihydrotestosterone in LNCaP cells. 1295 58

Androgens play a critical role in regulating the growth, differentiation and survival of epithelial cells in many androgen-responsive organs, such as prostate and skin. The enzyme steroid 5alpha-reductase (EC 1.3.99.5) catalyzes the conversion of testosterone (T) to a more active androgen, dihydrotestosterone (DHT). DHT then binds to androgen receptors (AR) and functions in the nucleus to regulate specific gene expression. Androgens via their cognate receptor may be involved in the development and progression of benign prostate hyperplasia, prostate cancer, hirsutism, male pattern alopecia and acne. The aim of this study was to determine whether theaflavin-3,3'-digallate (TF3) and penta-O-galloyl-beta-D-glucose (5GG) have inhibitory effects on androgen production and action. We found that TF3 and 5GG inhibit rat liver microsomal 5alpha-reductase activity. Furthermore, TF3 and 5GG significantly reduced androgen-responsive LNCaP prostate cancer cell growth, suppressed expression of the AR and lowered androgen-induced prostate-specific antigen secretion and fatty acid synthase protein level. In conclusion, our result suggests that TF3 and 5GG might be useful chemoprevention agents for prostate cancer through suppressing the function of androgen and its receptor.
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PMID:Theaflavin-3,3'-digallate and penta-O-galloyl-beta-D-glucose inhibit rat liver microsomal 5alpha-reductase activity and the expression of androgen receptor in LNCaP prostate cancer cells. 1496 12

Despite advances in the detection and management of prostate cancer, this disease remains a major cause of morbidity and mortality in men. Increasing attention has focused on the role of chemoprevention for prostate cancer, i.e., the administration of agents that inhibit one or more steps in the natural course of prostate carcinogenesis. We review prostate cancer chemoprevention studies in Europe. Published studies were identified in a search of MEDLINE. Information about ongoing studies was provided by author access to protocols. A variety of chemoprevention studies have focused on the role of dietary factors, vitamins, and trace elements in prostate cancer. Some of these studies have been prospective, randomized, and double-blinded, while others have used retrospective or epidemiological approaches. Large-scale randomized studies are also evaluating the role of 5alpha-reductase inhibitors, which inhibit the conversion of testosterone to the more potent androgen dihydrotestosterone. Robust evidence is lacking for the value of chemopreventive agents in prostate cancer. Current evidence does suggest that vitamin E and selenium may have a role in prostate cancer chemoprevention. Data from two studies, one examining the type 1 5alpha-reductase selective inhibitor finasteride and the other using the dual 5a-reductase inhibitor dutasteride, will determine the benefits of androgen inhibition strategies for prostate cancer chemoprevention.
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PMID:[Chemoprevention of prostate cancer]. 1504 90

Prostate cancer is a very common disease in industrialized countries and it is known to be androgen-dependent. The human SRD5A2 gene encodes the prostatic (or type II) steroid 5alpha-reductase, which catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate. We have sequenced the entire protein-coding region of this locus in 30 microdissected prostate adenocarcinomas. We identified a total of 17 de novo amino-acid substitutions in 13 of these tumors. We also identified six additional silent substitutions. In total, 18 out of 30 (60%) of the tumors examined had de novo somatic substitutions in the prostatic steroid 5alpha-reductase-coding region. We also characterized all of the SRD5A2 missense substitutions biochemically and pharmacologically, using three 5alpha-reductase inhibitors, including finasteride. The biochemical parameters of the distinct 5alpha-reductase missense substitutions varied substantially. We note that two out of the three recurrent SRD5A2 missense substitutions increased 5alpha-reductase in vitro activity, while the third one is essentially neutral. These findings are consistent with a role for increased DHT levels in the prostate through increased activity of the SRD5A2 locus in prostate cancer progression, in a subset of patients. Our pharmacologic studies also reveal substantial variability for each 5alpha-reductase inhibitor. These data, therefore, should be taken into account in both prevention as well as therapeutic trials of prostate cancer utilizing 5alpha-reductase inhibitors.
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PMID:Identification and characterization of somatic steroid 5alpha-reductase (SRD5A2) mutations in human prostate cancer tissue. 1532 87

After therapeutic hormone deprivation, most prostate cancer (PrCa) cells develop androgen-independent (AI) growth. PrCa is highly heterogeneous and multifocal, suggesting that several molecular processes or pathways may be contributing to AI. The human LuCaP 23.1 xenograft model retains clinical hallmarks of PrCa, including heterogeneous growth, PSA production, androgen-responsiveness and progression to AI. In this work, we studied the effect of androgen depletion (castration) on the growth of LuCaP 23.1 xenografts. A total of 100 nude mice were implanted and analysed for their growth profiles before and after castration. By 11 and 15 weeks, tumours were harvested and assessed for molecular marker expression specific for PrCa. Prior to castration we found 37 fast growing (FG) tumours (948.9+/-76.9 mm(3)) and 63 slow growing (SG) tumours (229.6+/-18.4 mm(3)), a previously undescribed result for this PrCa model. Quantitative RT-PCR showed that in comparison to SGs, FGs contained high HER1, uPA and thymidilate synthetase (TS) expression with low levels of 5alpha-reductase 2 mRNA. All FG tumours progressed rapidly to AI growth 5 weeks after castration (FG-P). In SG castrated tumours, 66% of tumours (SG-P) showed retarded progression (by 12 weeks) to AI, whereas 34% responded to castration (SG-R). Molecular analysis permitted us to define distinct molecular profiles integrating different pathways associated with AI progression. FG-P, and a subgroup of SG-P tumours, presented significantly high levels of peptidylglycine alpha-amidating monooxygenase (PAM), HER1, HER2, TS, and uPA mRNA, all of which correlated with AR expression. The second subgroup of SG-P tumours showed overexpression of the antiapoptotic gene Bcl-2. A third subgroup of SG-P tumours showed significant expression of hypoxia-related gene (adrenomedullin) after castration. This work permitted to define distinct molecular profiles related to different AI growth in the LuCaP 23.1 xenograft.
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PMID:Molecular analysis integrating different pathways associated with androgen-independent progression in LuCaP 23.1 xenograft. 1548 89

The concerns about testosterone therapy in ageing men with late-onset hypogonadism mainly address the risk of prostatic disease, i.e. either benign prostatic hyperplasia (BPH) or prostate cancer (PCa). Both conditions are highly dependent on androgen action and recent clinical data on the cancer-preventive effect of the 5alpha-reductase inhibitor finasteride have supported the possible role of androgens in PCa. However, the clinical data especially on the long-term effects of exogenous androgen substitution in regard to prostate safety are nonconclusive in many respects. As sufficient clinical studies on these risks will not be available in the near future, the approach of testosterone therapy towards prostate complications should be kept on a safe but practical basis. This review includes some recommendations in regard to testosterone therapy and prostate monitoring in patients with BPH and bladder outlet obstruction, with previous history of curative treatment for PCa or with prostatic intraepithelial neoplasia.
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PMID:Testosterone therapy in the ageing male: what about the prostate? 1554 Oct 51

The phytotherapeutic agent Serenoa repens is an effective dual inhibitor of 5alpha-reductase isoenzyme activity in the prostate. Unlike other 5alpha-reductase inhibitors, Serenoa repens induces its effects without interfering with the cellular capacity to secrete PSA. Here, we focussed on the possible pathways that might differentiate the action of Permixon from that of synthetic 5alpha-reductase inhibitors. We demonstrate that Serenoa repens, unlike other 5alpha-reductase inhibitors, does not inhibit binding between activated AR and the steroid receptor-binding consensus in the promoter region of the PSA gene. This was shown by a combination of techniques: assessment of the effect of Permixon on androgen action in the LNCaP prostate cancer cell line revealed no suppression of AR and maintenance of PSA protein expression at control levels. This was consistent with reporter gene experiments showing that Permixon failed to interfere with AR-mediated transcriptional activation of PSA and that both testosterone and DHT were equally effective at maintaining this activity. Our results demonstrate that despite Serenoa repens effective inhibition of 5alpha-reductase activity in the prostate, it did not suppress PSA secretion. Therefore, we confirm the therapeutic advantage of Serenoa repens over other 5alpha-reductase inhibitors as treatment with the phytotherapeutic agent will permit the continuous use of PSA measurements as a useful biomarker for prostate cancer screening and for evaluating tumour progression.
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PMID:Serenoa repens (Permixon) inhibits the 5alpha-reductase activity of human prostate cancer cell lines without interfering with PSA expression. 1554 14

Prostate cancer has an androgen-dependent growth mediated by the androgen receptor (AR). Androgen pathway blockage is the standard therapy for the treatment of prostate cancers at an advanced stage. In spite of an initial sensitivity, prostate cancers become more or less quickly towards androgen-independent. Hormone refractory can be due to amplification of AR gene, AR mutations and the increase in co-activator protein expression or in the 5alpha-reductase activity. These induce an agonist activity with the anti-androgens or others steroid hormones like estrogens on AR and allow AR activation with weak concentrations of androgens. Growth factors and cytokines can induce AR phosphorylation independently of the ligand fixation. In condition of androgenic deprivation, AR remains actively involved in the growth of the cancerous cells prostate. Nevertheless, there are others partial AR-independent pathways as neuroendocrine differentiation. The comprehension of these various mechanisms is the key of the development of more effective therapies on hormono-refractory prostate cancers.
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PMID:[Molecular mechanisms involved in hormone resistance of prostate cancer]. 1555 75


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