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)

1,25-(OH)(2) vitamin D(3) (1,25-(OH)(2) D), the active metabolite of vitamin D, exerts antiproliferative effects on a variety of tumor cells including prostate. This inhibition requires vitamin D receptors (VDRs) as well as downstream effects on the G1 to S phase checkpoint of the cell cycle. Recent data raise the possibility that androgen plays a role in the antiproliferative effects of 1,25-(OH)(2) D in prostate cancer cells; however, this hypothesis has been difficult to test rigorously as the majority of prostate cancer cell lines (unlike human prostate tumors) lack androgen receptors (ARs). We utilized two different models of androgen-independent prostate cancer that express functional ARs and VDRs to evaluate a possible role of androgen in 1,25-(OH)(2) D mediated growth inhibition. We stably introduced the AR cDNA into the human prostate cancer cell line ALVA 31, which expresses functional VDR but is relatively resistant to growth inhibition by 1,25-(OH)(2) D. Neither ALVA-AR nor the control cells, ALVA-NEO, exhibited substantial growth inhibition by 1,25-(OH)(2) D in the presence or absence of androgen. This observation suggests that the basis for the resistance of ALVA 31 to 1,25-(OH)(2) D-mediated growth inhibition is not the lack of AR. The second model was LNCaP-104R1, an AR-expressing androgen independent prostate cancer cell line derived from androgen dependent LNCaP. 1,25-(OH)(2) D inhibited the growth of LNCaP-104R1 cells in the absence of androgen and this effect was not blocked by the antiandrogen Casodex. As was observed in the parental LNCaP cells, this effect was correlated with G1 phase cell cycle accumulation and upregulation of the cyclin dependent kinase inhibitor (CKI) p27, as well as increased association of p27 with cyclin dependent kinase 2. These findings suggest that the antiproliferative effects of 1,25-(OH)(2) D do not require androgen-activated AR but do involve 1,25-(OH)(2) D induction of CKIs required for G1 cell cycle checkpoint control.
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PMID:Vitamin D-mediated growth inhibition of an androgen-ablated LNCaP cell line model of human prostate cancer. 1185 Jan 23

Epidemiological data indicate a relationship between ultraviolet radiation, vitamin D, and prostate cancer risk. Antiproliferative effects of vitamin D require the expression of the nuclear vitamin D receptor (VDR). A three-fold increase in prostate cancer risk associated with the less active vitamin D receptor allele (the T allele from VDR TaqI polymorphism at codon 352) was reported. The role of VDR genotypes in the susceptibility to prostate cancer has not yet been studied in populations of southern Europe. In the present study, we determined VDR TaqI genotypes in Portuguese prostate cancer cases ( n = 163) and controls ( n = 211), a southern European population. When cases were compared with controls, we found an association of VDR T allele with prostate cancer risk (odds ratio [OR] = 1.87, 95% confidence interval [CI] 1.02-3.37; P = 0.035). This association was confirmed using logistic regression analysis (OR = 2.11, 95% CI 1.15-3.88; P = 0.015) and in particular associated to risk of prostate cancer onset in men over the age of 66 years (OR = 2.36, 95% CI 1.05-5.29; P = 0.036). Fifty percent of cases older than 66 years could be attributed to the influence of this risk factor. Our results indicate that the contribution of VDR genotypes to prostate cancer susceptibility might depend on the population studied and its geographic localization, and that VDR genotypes are important in the definition of the genetic risk profile of populations of southern Europe.
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PMID:The role of vitamin D receptor gene polymorphisms in the susceptibility to prostate cancer of a southern European population. 1218 42

Epidemiologic data suggest that low exposure to vitamin D or 1alpha,25-dihydroxycholecalciferol (calcitriol) increases the risk of prostate cancer. Calcitriol, a central factor in bone and mineral metabolism, is also a potent antiproliferative agent in a wide variety of malignant cell types. We have demonstrated that calcitriol has significant antitumor activity in vitro and in vivo in prostate and squamous cell carcinoma model systems. Calcitriol, in these models, induces a significant G0/G1 arrest and modulates p21(Waf1/Cip1) and p27(Kip1), the cyclin-dependent kinase inhibitors. Calcitriol induces poly (adenosine diphosphate-ribose) polymerase cleavage, increases bax/bcl-2 ratio, reduces levels of phosphorylated mitogen-activated protein kinases (P-MAPKs; also known as extracellular signal-related kinase [ERK] 1/2) and phosphorylated Akt, induces caspase-dependent mitogen-activated protein kinase kinase (MEK) cleavage and upregulation of MEK kinase-1, all potential markers of the apoptotic pathway. We also have demonstrated that dexamethasone (dex) potentiates the antitumor effect of calcitriol through effects on the vitamin D receptor and decreases calcitriol-induced hypercalcemia. We initiated phase 1 and phase 2 trials of calcitriol, either alone or in combination with carboplatin, paclitaxel, or dex. Data from these studies indicate that high-dose calcitriol is feasible on an intermittent schedule, the maximum tolerated dose (MTD) is unclear, and dex or paclitaxel appear to ameliorate hypercalcemia. Studies continue to define the MTD of calcitriol on this intermittent schedule, either alone or with other agents, and to evaluate the mechanisms of calcitriol effects in prostate cancer models.
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PMID:Vitamin D receptor: a potential target for intervention. 1223 Oct 68

Calcitriol [1alpha,25-dihydroxyvitamin D3] is the natural ligand of the vitamin D receptor (VDR). Using cultured prostate cancer (PC) cell lines, LN-CaP and ALVA-31, we studied the effects of 1alpha,25(OH)2-Vitamin D3 (VD3) on expression of several apoptosis-regulating proteins including: (a) Bcl-2 family proteins (Bcl-2, Bcl-X(L), Mcl-1, Bax, and Bak); (b) the heat shock protein 70-binding protein BAG1L; and (c) IAP family proteins (XIAP, cIAP1, and cIAP2). VD3 induced decreases in levels of antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1, BAG1L, XIAP, cIAP1, and cIAP2 (without altering proapoptotic Bax and Bak) in association with increases in apoptosis. In contrast to VDR-expressing LN-CaP and ALVA-31 cells, VDR-deficient prostate cancer line Du-145 demonstrated no changes in apoptosis protein expression after treatment with VD3. In sensitive PC cell lines, VD3 activates downstream effector protease, caspase-3, and upstream initiator protease caspase-9, the apical protease in the mitochondrial ("intrinsic") pathway for apoptosis, but not caspase-8, an initiator caspase linked to an alternative ("extrinsic") apoptosis pathway triggered by cytokine receptors. VD3 induced declines in antiapoptotic proteins and also stimulated cytochrome c release from mitochondria by a caspase-independent mechanism. Moreover, apoptosis induction by VD3 was suppressed by overexpressing Bcl-2, a known blocker of cytochrome c release, whereas the caspase-8 suppressor CrmA afforded little protection. Thus, VD3 is capable of inhibiting expression of multiple antiapoptotic proteins in VDR-expressing prostate cancer cells, leading to activation of the mitochondrial pathway for apoptosis.
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PMID:Apoptosis induction by 1alpha,25-dihydroxyvitamin D3 in prostate cancer. 1247 63

Vitamin D plays an important role in cell growth and differentiation and is proposed to protect against cancer initiation and/or progression. The vitamin D receptor (VDR) has a thymine/cytosine (T/C) polymorphism located in the first of two potential start (ATG) codons that can be detected by a RFLP using the endonuclease FokI. The C variant, which lacks the first ATG, results in a shorter VDR and is referred to as the F allele. The T variant (f allele) initiates at the first ATG. We examined the association of the VDR FokI genotype with histopathological characteristics and prognosis of prostate cancer among 191 mostly Caucasian subjects who had undergone radical prostatectomy between 1984 and 1992. The frequencies of the FF, Ff, and ff genotypes were 41%, 38%, and 21%, respectively. Subjects with the ff genotype had a lower mean percentage of Gleason grade 4/5 cancer (30.3%) than subjects with the FF or Ff genotypes (42.8% and 43.8%, respectively; P = 0.015 by t test for ff versus FF + Ff). The data suggest that the presence of an F allele increased the risk of being diagnosed with more aggressive cancer because higher percentage of Gleason grade 4/5 is associated with worse prognosis. The age-adjusted risk of prostate-specific antigen failure was lower for the ff genotype than for the FF genotype by Cox proportional hazards analysis but did not achieve statistical significance (hazard ratio = 0.76; 95% confidence interval, 0.44-1.32). This risk reduction disappeared after further adjustment for percentage of Gleason grade 4/5, cancer volume, and preoperative serum prostate-specific antigen level (hazard ratio = 1.03; 95% confidence interval, 0.58-1.85). In conclusion, the ff genotype was associated with less aggressive histopathological findings than Ff or FF genotypes. Additional studies with a larger sample size and investigation of the functional significance of the FokI polymorphism in prostate cancer cells are warranted.
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PMID:Vitamin D receptor start codon polymorphism (FokI) and prostate cancer progression. 1254 Apr 99

Prostate cancer (PRCa) is one of the most common causes of cancer death in men and determinants of PRCa risk remain largely unidentified. Benign prostatic hyperplasia (BPH) is found in the majority of ageing men and has been associated with PRCa. Many candidate genes have been suggested to be involved in PRCa, such as those that are central to cellular growth and differentiation in the prostate gland. The vitamin D receptor (VDR) and CYP3A4 have been shown to be involved in the regulation of cell proliferation and differentiation in prostate cells. Genetic variations of these genes have been associated with PRCa in case-control studies and may be useful to detect BPH patients that have a higher risk of developing PRCa. The association between CYP3A4 and VDR TaqI SNPs and the risk of developing PRCa have been investigated in this study by determining the variant genotype frequencies of both SNPs in 400 patients with BPH who have been followed clinically for a median of 11 years. The results of this study showed that the incidence rate of PRCa was higher in BPH patients having CYP3A4 variant genotype compared to those with wild type (relative risk (RR)=2.7; 95% CI=0.77-7.66). No association between variant genotype and risk of developing PRCa was observed with the VDR TaqI variant genotype. In addition, the results of combined genotype analysis of these two SNPs showed a borderline significant association between CYP3A4 and VDR TaqI combined variant genotypes and PRCa risk (RR=3.43; 95% CI=0.99-11.77). While independent confirmation is required in further studies, these results provide a potential tool to assist prediction strategies for this important disease.
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PMID:CYP3A4 and VDR gene polymorphisms and the risk of prostate cancer in men with benign prostate hyperplasia. 1264 31

A multigenic model of prostate cancer susceptibility has been proposed, in which common polymorphic variants of genes, such as the androgen and vitamin D receptor, contribute to tumorigenesis. The discovery of additional genetic factors that contribute to prostate cancer risk should provide opportunities for new approaches to the detection and treatment of this common malignancy. Herein, we examined single nucleotide polymorphic variants in the 3'-untranslated region of CDKN1A (p21(cip1)) and in codon 109 of CDKN1B (p27(kip1)) for association with advanced prostate cancer in a European-American population. Ninety-six cases and 106 controls were analyzed using PCR amplification and restriction digestion assays. CDKN1A genotype was scored as CC, CT, and TT on the basis of the digestion products. The CDKN1A genotypes CT and TT were associated with an increased risk of advanced prostate carcinoma compared with the CC genotype [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.02-4.95]. The CDKN1B genotype was scored as VV, VG, or GG, again on the basis of the digestion products. The CDKN1B genotype VV was also associated with an increased risk of advanced prostate carcinoma (OR, 1.95; 95% CI, 1.09-3.47). These associations were particularly strong in those patients with androgen-independent disease [OR = 2.88 (95% CI, 1.19-6.97) and 2.11 (95% CI, 1.05-4.22) for high-risk genotypes of CDKN1A and CDKN1B, respectively]. In addition, the association of CDKN1B was particularly strong in the cohort of patients under the median age of diagnosis (OR, 2.23; 95% CI, 1.08-4.59). These results suggest that in a European-American population, CDKN1A and CDKN1B variants are associated with advanced prostate cancer. Analysis of CDKN1A and/or CDKN1B genotypes may prove useful in determining which patients are at risk for developing advanced prostate carcinoma and therefore would gain the most from aggressive screening, prophylaxis, and/or treatment.
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PMID:CDKN1A and CDKN1B polymorphisms and risk of advanced prostate carcinoma. 1272 15

1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) and its derivatives are a potential treatment of human prostate cancer. The antiproliferative action of 1alpha,25(OH)(2)D(3) is mainly exerted through nuclear vitamin D receptor (VDR)-mediated control of target gene transcription. To explore the target genes which are regulated by 1alpha,25(OH)(2)D(3) in human prostate cancer LNCaP cells, cDNA microarray was performed by using a chip that contains 3000 gene probes. The results showed that 24 genes were regulated by 1alpha,25(OH)(2)D(3). Five of them encode proteins which belong to metabolic enzymes and fatty acid biosynthesis. Fatty acid synthase (FAS) was found to be down-regulated by 1alpha,25(OH)(2)D(3), and the regulation was confirmed by real-time quantitative RT-PCR analysis. Inhibition of FAS expression by 1alpha,25(OH)(2)D(3) in LNCaP cells was more than 50% at 6h. Inhibitory effect of 1alpha,25(OH)(2)D(3) on FAS expression was completely blocked in the presence of protein synthesis inhibitor cycloheximide, indicating that the down-regulation of FAS gene expression by 1alpha,25(OH)(2)D(3) was indirect in LNCaP cells. An inhibition of FAS activity by cerulenin resulted in a strong inhibition of LNCaP cell proliferation. The inhibition of FAS expression and cell proliferation by 1alpha,25(OH)(2)D(3) seemed to be androgen-dependent, since antiandrogen, casodex and DCC-treatment of serum blocked the vitamin D action. The findings suggest that FAS is involved in the antiproliferative effect of 1alpha,25(OH)(2)D(3) in presence of androgens on prostate cancer LNCaP cells.
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PMID:Inhibition of fatty acid synthase expression by 1alpha,25-dihydroxyvitamin D3 in prostate cancer cells. 1279 52

Parathyroid hormone-related protein (PTHrP) is expressed by prostate cancer cells. Since PTHrP increases the growth and enhances the osteolytic effects of prostate cancer cells, it is important to control the level of PTHrP expression in these cells. We show that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its non-calcemic analogue, EB1089, suppress PTHrP mRNA and protein levels in the human prostate cancer cell lines PC-3 and LNCaP. The human PTHrP gene contains a sequence element homologous to the negative vitamin D response element within the parathyroid hormone gene. This DNA sequence (nVDRE(hPTHrP)) bound the vitamin D receptor (VDR) present in nuclear extracts from both PC-3 and LNCaP cells. However, when cloned upstream of the SV40 promoter and transiently transfected into PC-3 and LNCaP cells, nVDRE(hPTHrP) downregulated promoter activity in response to 1,25(OH)2D3 or EB1089 treatment in LNCaP, but not in PC-3, cells. These results may help to explain why some prostate cancers appear to be refractory to treatment with vitamin D analogues.
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PMID:Prostate cancer cell type-specific regulation of the human PTHrP gene via a negative VDRE. 1285 Feb 81

Breast and prostate cancer are leading causes of cancer death in the Western world. Hormone ablation is the primary therapy for invasive disease, but the tumour often recurs in an androgen or oestrogen receptor negative form for which novel therapies are sought urgently. The vitamin D receptor (VDR) may provide an important alternative therapeutic target. However, cancer cell line models from these tissues display a range of sensitivities to the antiproliferative effects of 1alpha,25dihydroxyvitamin D3 (1alpha,25(OH)2D3). The reason for apparent 1alpha,25(OH)2D3 insensitivity is currently unknown and we have investigated epigenetic mechanisms that may suppress the transcriptional activity of the VDR. Nuclear co-repressors have associated histone deacetylase (HDAC) activity, which keeps chromatin in a closed, transcriptionally silent state. We have found that the aggressive cancer cell lines with relative insensitivity to 1alpha,25(OH)2D3 have elevated nuclear co-repressor levels. For example, PC-3 prostate cancer cells have a significant 1.8-fold elevation in the co-repressor SMRT compared to normal epithelial cells (P < 0.05). We believe that a combination of elevated co-repressor level with reduced VDR content can cause 1alpha,25(OH)2D3 resistance. Consistent with this, we have shown that combining a low dose of HDAC inhibitor Trichostatin A (15 nM TSA) with 1alpha,25(OH)2D3 (100 nM) synergistically inhibits the proliferation of PC-3 prostate and MDA-MB-231 breast cancer cell lines. The inhibition of proliferation was potentiated further by treating cells with 19-nor-hexafluoride vitamin D3 analogues instead of 1alpha,25(OH)2D3, plus TSA. For example, the combination of 1alpha,25(OH)2D3 and TSA-inhibited MDA-MB-231 cell proliferation by 38% (+/-5%), whereas Ro26-2198 (1alpha,25-(OH)2-16,23Z-diene-26,27-F6-19-nor-D3) and TSA inhibited growth by 62% (+/-2%). Therapeutically the hypercalcaemic side effects associated with 1alpha,25(OH)2D3 could be minimized by combining low doses of potent 1a,25(OH)2D3 analogues with HDAC inhibitors as a novel anticancer regime for hormone-insensitive prostate and breast cancer.
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PMID:Antiproliferative signalling by 1,25(OH)2D3 in prostate and breast cancer is suppressed by a mechanism involving histone deacetylation. 1289 15


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