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)

Prostatic cells express vitamin D receptor (VDR), which mediates the functions of 1,25-dihydroxyvitamin D. Two recent case-control studies suggested strong inverse associations between two VDR polymorphisms, TaqI and poly(A), and risk of prostate cancer. These two and a third polymorphism, BsmI, are closely linked. In a case-control study nested in the Physicians' Health Study, a randomized double-blind trial of aspirin and beta-carotene among 22,071 United States male physicians, we examined the associations between BsmI and TaqI and prostate cancer risk and whether the associations varied according to age and vitamin D metabolite levels among 372 incident cases and 591 controls. Among controls, the BB genotype was significantly associated with higher 1,25-dihydroxyvitamin D (median = 36.2 pg/ml for the BB versus 33.9 pg/ml for the bb genotype; P = 0.02), suggesting an association of the VDR polymorphisms with VDR function. Overall, we observed no significant associations of these VDR polymorphisms with prostate cancer risk: relative risk (RR) = 0.86 [95% confidence interval (CI) = 0.57-1.29] for the BB genotype and RR = 0.92 (95% CI = 0.69-1.22) for the Bb genotype, compared with the bb genotype (results were similar for the TaqI polymorphism). Stratification by age (< or = 61 and > 61 years) and tumor aggressiveness showed no significant associations. However, in an analysis restricted to men with plasma 25-hydroxyvitamin D below the median, we observed a 57% reduction (RR = 0.43, 95% CI = 0.19-0.98) in risk for those with the BB versus the bb genotype; the risk reduction was particularly marked among older men (RR = 0.18, 95% CI = 0.05-0.68). We did not observe this inverse association among men with 25-hydroxyvitamin D levels above the median, nor did we observe it among younger men.
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PMID:Vitamin D receptor polymorphisms, circulating vitamin D metabolites, and risk of prostate cancer in United States physicians. 961 Jul 87

Calcitrol, 1,25 dihydroxyvitamin D3 (1,25-D3) has an important role in the antiproliferative and growth regulatory effects on normal and neoplastic cells (e.g. prostate cancer cells). 1,25-D3 binds to the vitamin D receptor (VDR), a member of the steroid receptor superfamily. Steroids, via intranuclear receptors, have been demonstrated to have high affinity binding to the nuclear matrix, the tissue specific scaffolding of the nucleus that is involved in the organization of DNA, replication and transcription. We hypothesized that the VDR interacts closely with the nuclear matrix in both human and rat tissues. In the studies described here, nuclear matrix proteins (NMP) were extracted from a number of rat and human tissues and immunoblot analysis performed using a rat anti-VDR antibody. The results from these studies reveal that the anti-VDR antibody detects six forms of the VDR in the NMP preparations: human testis demonstrated a protein of 57 and 52 kDa molecular weight compared with 57 and 37 kDa in the rat testis. Human prostate demonstrated proteins of 52 kDa compared to rat ventral (57 and 37 kDa) and dorsal prostate (52 and 26 kDa). Human and rat bladder NMP demonstrated a protein binding at 55 kDa and rat seminal vesicle NMP binding at 48 kDa. This is the first report of VDRs associated with the nuclear matrix. The varying molecular weight proteins reactive with the anti-VDR antibody within these tissues may represent different isoforms, proteolytic cleavage of a larger VDR or post-translational modification. The VDR-NMP interaction may be involved in the tissue specific actions of 1,25-D3 especially growth regulatory and antiproliferative effects.
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PMID:Association of vitamin D receptors with the nuclear matrix of human and rat genitourinary tissues. 974 21

Numerous studies have indicated that the secosteroid hormone 1alpha, 25-dihydroxyvitamin D3 protects against the development of clinical prostate cancer (PC). Whether this hormone also has therapeutic potential for patients with advanced PC has not yet been evaluated. Several synthetic vitamin D analogues are now available that have reduced hypercalcemic effects and yet effectively induce differentiation in some cell types. For these reasons, these analogues may be safer and more effective for cancer therapy than the natural hormone. In the current study, 13 such analogues were screened for their abilities to inhibit the growth of PC cell lines. Three of the most consistently effective analogues (Ro 23-7553, Ro 24-5531, and Ro 25-6760) were then chosen for further analysis. Growth studies using clones of the JCA-1 cell line that were transfected with the vitamin D receptor cDNA indicate that the antiproliferative effects of these analogues require vitamin D receptor expression. Furthermore, these three analogues induce the secretion of prostate-specific acid phosphatase and prostate-specific antigen (two markers of the differentiated prostatic phenotype) in the cell line LNCaP. These in vitro studies suggest that Ro 23-7553, Ro 24-5531, and Ro 25-6760 should be further evaluated as therapeutic agents for the treatment of PC.
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PMID:Three synthetic vitamin D analogues induce prostate-specific acid phosphatase and prostate-specific antigen while inhibiting the growth of human prostate cancer cells in a vitamin D receptor-dependent fashion. 981 16

Although prostatic cancer is often viewed as an androgen-dependent malignancy, a number of other hormones including 1alpha, 25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] are now recognized to modulate its growth and differentiated phenotype. Seven different continuous human prostatic carcinoma cell lines were examined for the presence of biologically active receptors for 1alpha,25(OH)2D3. All seven lines were found to contain mRNA for the vitamin D receptor using an RNase protection assay. Six of the seven cell lines were found to have high-affinity saturable binding sites for 1alpha,25(OH)2D3. The seventh line was found to contain vitamin D receptors by sucrose gradient analysis. All seven lines were found to express 24-hydroxylase activity by a HPLC assay that measures the conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3. 24-Hydroxylase activity was up-regulated in all seven cell lines by preincubation with 1alpha,25(OH)2D3. In the presence of fetal bovine serum, the growth of four of the seven cell lines was inhibited. In the majority of cell lines growth inhibition was related not only to the number of receptors per cell, but also in inverse proportion to the 24-hydroxylase activity of each cell line. The ubiquitous presence of vitamin D receptor and 24-hydroxylase activity in human prostatic carcinoma cells suggests new alternatives for the pharmacological treatment of advanced prostatic cancer and implies that chemoprevention strategies could also make use of this endocrine axis.
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PMID:Vitamin D receptor expression, 24-hydroxylase activity, and inhibition of growth by 1alpha,25-dihydroxyvitamin D3 in seven human prostatic carcinoma cell lines. 981 72

Allelic variation at the 3'-end of the vitamin D receptor (VDR) gene has been associated with a 3-5-fold increased risk of developing prostate cancer and with differences in bone mineralization. This genetic diversity does not alter the VDR protein structurally, but instead may be a marker(s) of other, nearby polymorphisms that influence message stability or translation. The work reported here was instigated to identify additional VDR 3'-UTR polymorphisms that may have functional significance and to then test whether these genetic variants alter message stability. Initially, four novel, frequently occurring sequence variants were identified that associated with two common haplotypes that were described previously. These common sequence variants were not found within three message-destabilizing elements that we mapped within the 3'-UTR of the vitamin D receptor mRNA. Furthermore, the two VDR 3'-UTR haplotypes conferred an identical half-life on a heterologous beta-globin reporter gene, in an in vitro assay. We therefore conclude that common polymorphisms within the VDR 3'-UTR do not influence message stability.
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PMID:Vitamin D receptor 3'-untranslated region polymorphisms: lack of effect on mRNA stability. 1010 Dec 49

1Alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] inhibits the proliferation of many cancer cells in culture, but not the aggressive human prostate cancer cell line DU 145. We postulated that the 1,25-(OH)2D3-resistant phenotype in DU 145 cells might result from the high levels of expression of 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) induced by treatment with 1,25-(OH)2D3. As this P450 enzyme initiates 1,25-(OH)2D3 catabolism, we presumed that a high level of enzyme induction could limit the effectiveness of the 1,25-(OH)2D3 antiproliferative action. To examine this hypothesis we explored combination therapy with liarozole fumarate (R85,246), an imidazole derivative currently in trials for prostate cancer therapy. As imidizole derivatives are known to inhibit P450 enzymes, we postulated that this drug would inhibit 24-hydroxylase activity, increasing the 1,25-(OH)2D3 half-life, thereby enhancing 1,25-(OH)2D3 antiproliferative effects on DU 145 cells. Cell growth was assessed by measurement of viable cells using the MTS assay. When used alone, neither 1,25-(OH)2D3 (1-10 nM) nor liarozole (1-10 microM) inhibited DU 145 cell growth. However, when added together, 1,25-(OH)2D3 (10 nM)/liarozole (1 microM) inhibited growth 65% after 4 days of culture. We used a TLC method to assess 24-hydroxylase activity and demonstrated that liarozole (1-100 microM) inhibited this P450 enzyme in a dose-dependent manner. Moreover, liarozole treatment caused a significant increase in 1,25-(OH)2D3 half-life from 11 to 31 h. In addition, 1,25-(OH)2D3 can cause homologous up-regulation of the vitamin D receptor (VDR), and in the presence of liarozole, this effect was amplified, thus enhancing 1,25-(OH)2D3 activity. Western blot analyses demonstrated that DU 145 cells treated with 1,25-(OH)2D3/liarozole showed greater VDR up-regulation than cells treated with either drug alone. In summary, our data demonstrate that liarozole augments the ability of 1,25-(OH)2D3 to inhibit DU 145 cell growth. The mechanism appears to be due to inhibition of 24-hydroxylase activity, leading to increased 1,25-(OH)2D3 half-life and augmentation of homologous up-regulation of VDR. We raise the possibility that combination therapy using 1,25-(OH)2D3 and liarozole or other inhibitors of 24-hydroxylase, both in nontoxic doses, might serve as an effective treatment for prostate cancer.
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PMID:Liarozole acts synergistically with 1alpha,25-dihydroxyvitamin D3 to inhibit growth of DU 145 human prostate cancer cells by blocking 24-hydroxylase activity. 1021 56

Vitamin D receptor gene polymorphism was determined in 66 and 60 Japanese patients with prostate cancer and non cancer controls, respectively. In contrast to previous reports showing an association between vitamin D receptor polymorphism of a TaqI restriction fragment length polymorphism at codon 352 (genotype tt) and prostate cancer in an American population, the frequency of genotype tt is less than one percent in the Japanese population. There was no difference between the patients and the controls in the vitamin D receptor TaqI genotype. In patients with metastatic prostate cancer, genotype TT had a tendency to shorter progression free survival compared to genotype Tt, but the number of patients was limited.
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PMID:Vitamin D receptor gene polymorphism in Japanese patients with prostate cancer. 1050 1

Breast cancer is the leading cause of cancer death among Australian women and its incidence is annually increasing. Genetic factors are involved in the complex etiology of breast cancer. The seco-steroid hormone, 1.25 dihydroxy vitamin D3 can influence breast cancer cell growth in vitro. A number of studies have reported correlations between vitamin D receptor (VDR) gene polymorphisms and several diseases including prostate cancer and osteoporosis. In breast cancer, low vitamin D levels in serum are correlated with disease progression and bone metastases, a situation also noted in prostate cancer and suggesting the involvement of the VDR. In our study, 2 restriction fragment length polymorphisms (RFLP) in the 3' region (detected by Apa1 and Taq1) and an initiation codon variant in the 5' end of the VDR gene (detected by Fok1) were tested for association with breast cancer risk in 135 females with sporadic breast cancer and 110 cancer-free female controls. Allele frequencies of the 3' Apa1 polymorphism showed a significant association (p = 0.016; OR = 1.56, 95% CI = 1.09-2.24) while the Taq1 RFLP showed a similar trend (p = 0.053; OR = 1.45, 95% CI = 1.00-2.00). Allele frequencies of the Fok1 polymorphism were not significantly different (p = 0.97; OR = 0.99, 95% CI = 0.69-1.43) in the study population. Our results suggest that specific alleles of the VDR gene located near the 3' region may identify an increased risk for breast cancer and justify further investigation of the role of VDR in breast cancer.
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PMID:Association of A vitamin D receptor polymorphism with sporadic breast cancer development. 1059 85

While the role of vitamin D in bone and mineral metabolism has been investigated extensively, the role of the vitamin D receptor in other tissues is less well understood. 1,25-Dihydroxyvitamin D3 (calcitriol) can act as a differentiating agent in normal tissues and can inhibit the growth of many cancer cell lines including LNCaP prostate cancer cells. We have shown previously that calcitriol causes LNCaP cell accumulation in the G0/G1 phase of the cell cycle. In this study, we demonstrate that calcitriol also induces apoptosis of LNCaP cells. The calcitriol-induced apoptosis is accompanied by a down-regulation of Bcl-2 and Bcl-X(L) proteins, both of which protect cells from undergoing apoptosis. Other proteins important in apoptotic control, Bax, Mcl-1, and Bcl-X(S), are unaffected by calcitriol treatment. We find that overexpression of Bcl-2 blocks calcitriol-induced apoptosis and reduces, but does not eliminate, calcitriol-induced growth inhibition. We conclude that both regulation of cell cycle and the apoptotic pathway are involved in calcitriol action in prostate cancer cells.
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PMID:Calcitriol-induced apoptosis in LNCaP cells is blocked by overexpression of Bcl-2. 1061 17

Prostate cancer is a common disease, yet determinants of prostate cancer risk remain largely unidentified. Low circulating levels of 1, 25-dihydroxy vitamin D (1,25-D) have been implicated as a risk factor for prostate cancer. In addition, 1,25-D exhibits significant antineoplastic properties both in vitro and in vivo, and these antiproliferative effects appear to be mediated through the vitamin D receptor (VDR). The VDR has a number of common polymorphisms, including a TaqI restriction fragment length polymorphism in exon 9 and a poly(A) length polymorphism in the 3'-untranslated region. Previous studies have found an association between the TaqI T allele or poly(A) L allele and prostate cancer. To further investigate the putative link between VDR polymorphisms and prostate cancer, we conducted a case-control study of prostate cancer patients from the Piedmont region of North Carolina. Using polymerase chain reaction-based techniques on DNA extracted from peripheral blood, we genotyped 77 cases (70 white, seven black) and 183 controls (169 white, 14 black) for the TaqI and poly(A) alleles. We report here an overall lack of association between either the TaqI or poly(A) genotype and prostate cancer odds ratio (OR)=1.4, 95% confidence interval (CI)=0.7-2.8; and OR=1.2, 95% CI=0.6-2.5, respectively). Using a case-case analysis, we tested whether these polymorphisms might be associated with more advanced disease but found no statistically significant association for the TaqI T or poly(A) L allele (OR=2.5, 95% CI=0.3-21.7; OR=2.8, 95% CI=0.3-23.8, respectively). We report strong evidence of linkage disequilibrium between the TaqI and poly(A) polymorphisms (P < 0.0001), with whites demonstrating stronger linkage disequilibrium than blacks (D=0.24 vs. D=0.18).
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PMID:Vitamin D receptor polymorphisms and prostate cancer. 1064 33


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