UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vitamin D receptor (VDR) is a member of the steroid/retinoid receptor superfamily of nuclear receptors and has potential tumor-suppressive functions in prostate and other cancer types. Vitamin D3 (VD3) exerts its biological actions by binding within cells to VDR. The VDR then interacts with specific regions of the DNA in cells, and triggers changes in the activity of genes involved in cell division, cell survival, and cellular function. Using human primary cultures and the prostate cancer (PCa) cell line, ALVA-31, we examined the effects of VD3 under different culture conditions. Complete G0/G1 arrest of ALVA-31 cells and approximately 50% inhibition of tumor stromal cell growth was observed. To determine changes in gene expression patterns related to VD3 activity, microarray analysis was performed. More than approximately 20,000 genes were evaluated for twofold relative increases and decreases in expression levels. A number of the gene targets that were up- and down-regulated are related to potential mechanisms of prostatic growth regulation. These include estrogen receptor (ER), heat shock proteins: 70 and 90, Apaf1, Her-2/neu, and paxillin. Utilizing antibodies generated against these targets, we were able to confirm the changes at the protein level. These newly reported gene expression patterns provide novel information not only potential markers, but also on the genes involved in VD3 induced apoptosis in PCa.
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PMID:Vitamin D3 modulated gene expression patterns in human primary normal and cancer prostate cells. 1536 55

Vitamin D seems to be an important determinant of prostate cancer risk and inherited polymorphisms in the 3'untranslated region of the vitamin D receptor (VDR) gene have been associated with the risk and progression of prostate cancer in some populations. We therefore studied VDR gene polymorphisms, as detected by Apal and Taql restriction fragments, in multiethnic Brazilian men (165 patients and 200 controls) for association with prostate cancer risk and parameters of disease severity (serum PSA, Gleason score and tumor stage). No statistical correlations were found. The unique ethnical background of Brazilian subjects, characterized by an extensive racial mixture of European, African-American and Native American, might have blunted any ethnic-specific significance of VDR polymorphisms. Further investigations of the associations between VDR and other genetic or environmental factors are warranted.
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PMID:Vitamin D receptor polymorphisms and prostate cancer risk in Brazilian men. 1550 28

The aberrant behavior of cancer reflects upregulation of certain oncogenic signaling pathways that promote proliferation, inhibit apoptosis, and enable the cancer to spread and evoke angiogenesis. Theoretically, it should be feasible to decrease the activity of these pathways-or increase the activity of pathways that oppose them-with noncytotoxic agents. Since multiple pathways are dysfunctional in most cancers, and cancers accumulate new oncogenic mutations as they progress, the greatest and most durable therapeutic benefit will likely be achieved with combination regimens that address several targets. Thus, a multifocal signal modulation therapy (MSMT) of cancer is proposed. This concept has already been documented by researchers who have shown that certain combinations of signal modulators-of limited utility when administered individually-can achieve dramatic suppression of tumor growth in rodent xenograft models. The present essay attempts to guide development of MSMTs for prostate cancer. Androgen ablation is a signal-modulating measure already in standard use in the management of delocalized prostate cancer. The additional molecular targets considered here include the type 1 insulin-like growth factor receptor, the epidermal growth factor receptor, mammalian target of rapamycin, NF-kappaB, hypoxia-inducible factor-1alpha, hsp90, cyclooxygenase-2, protein kinase A type I, vascular endothelial growth factor, 5-lipoxygenase, 12-lipoxygenase, angiotensin II receptor type 1, bradykinin receptor type 1, c-Src, interleukin-6, ras, MDM2, bcl-2/bclxL, vitamin D receptor, estrogen receptor-beta, and PPAR-. Various nutrients and phytochemicals suspected to have potential utility in prostate cancer prevention and therapy, but whose key molecular targets are still unknown, might reasonably be incorporated into MSMTs for prostate cancer; these include lycopene, selenium, green tea polyphenols, genistein, and silibinin. MSMTs can be developed systematically by testing various combinations of signal-modulating agents, in concentrations that can feasibly be achieved and maintained clinically, on human prostate cancer cell lines; combinations that appear promising can then be tested in xenograft models and, ultimately, in the clinic. Some signal modulators can increase response to cytotoxic drugs by upregulating effectors of apoptosis. When MSMTs fail to raise the spontaneous apoptosis rate sufficiently to achieve tumor stasis or regression, incorporation of appropriate cytotoxic agents into the regimen may improve the clinical outcome.
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PMID:Targeting multiple signaling pathways as a strategy for managing prostate cancer: multifocal signal modulation therapy. 1552 6

The 25-hydroxyvitamin D(3) (25-OH-D(3)) is a nontoxic and low-affinity vitamin D receptor (VDR)-binding metabolic precursor of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. We hypothesized that covalent attachment of a 25-OH-D(3) analog to the hormone-binding pocket of VDR might convert the latter into transcriptionally active holo-form, making 25-OH-D(3) biologically active. Furthermore, it might be possible to translate the nontoxic nature of 25-OH-D(3) into its analog. We showed earlier that 25-hydroxyvitamin D(3)-3-bromoacetate (25-OH-D(3)-3-BE) alkylated the hormone-binding pocket of VDR. In this communication we describe that 10(-6) mol/L of 25-OH-D(3)-3-BE inhibited the growth of keratinocytes, LNCaP, and LAPC-4 androgen-sensitive and PC-3 and DU145 androgen-refractory prostate cancer cells, and PZ-HPV-7 immortalized normal prostate cells with similar or stronger efficacy as 1,25(OH)(2)D(3). But its effect was strongest in LNCaP, PC-3, LAPC-4, and DU145 cells. Furthermore, 25-OH-D(3)-3-BE was toxic to these prostate cancer cells and caused these cells to undergo apoptosis as shown by DNA-fragmentation and caspase-activation assays. In a reporter assay with COS-7 cells, transfected with a 1alpha,25-dihydroxyvitamin D(3)-24-hydroxylase (24-OHase)-construct and VDR-expression vector, 25-OH-D(3)-3-BE induced 24-OHase promoter activity. In a "pull down assay" with PC-3 cells, 25-OH-D(3)-3-BE induced strong interaction between VDR and general transcription factors, retinoid X receptor, and GRIP-1. Collectively, these results strongly suggested that the cellular effects of 25-OH-D(3)-3-BE were manifested via 1,25(OH)(2)D(3)/VDR signaling pathway. A toxicity study in CD-1 mice showed that 166 microg/kg of 25-OH-D(3)-3-BE did not raise serum-calcium beyond vehicle control. Collectively, these results strongly suggested that 25-OH-D(3)-3-BE has a strong potential as a therapeutic agent for androgen-sensitive and androgen-refractory prostate cancer.
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PMID:Inhibition of proliferation and induction of apoptosis by 25-hydroxyvitamin D3-3beta-(2)-Bromoacetate, a nontoxic and vitamin D receptor-alkylating analog of 25-hydroxyvitamin D3 in prostate cancer cells. 1558 37

1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the active metabolite of vitamin D(3), is known for the maintenance of mineral homeostasis and normal skeletal architecture. However, apart from these traditional calcium-related actions, 1,25-(OH)(2)D(3) and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities. These actions of 1,25-(OH)(2)D(3) are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25-(OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, actinic keratosis, seborrheic dermatitis, photoaging), osteoporosis (postmenopausal and steroid-induced osteoporosis), cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), secondary hyperparathyroidism, and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation). As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, encouraging results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma. This review deals with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.
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PMID:Noncalcemic actions of vitamin D receptor ligands. 1579 98

Peroxisome proliferator-activated receptor (PPAR) delta is the most widely expressed member of the PPAR family of nuclear receptor fatty acid sensors. Real-time PCR analysis of breast and prostate cancer cell lines demonstrated that PPARdelta expression was increased 1.5 to 3.2-fold after three hours stimulation with the natural vitamin D receptor (VDR) agonist, 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3). In silico analysis of the 20 kb of the human PPARdelta promoter revealed a DR3-type 1alpha,25(OH)2D3 response element approximately 350 bp upstream of the transcription start site, which was able to bind VDR-retinoid X receptor (RXR) heterodimers and mediate a 1alpha,25(OH)2D3-dependent upregulation of reporter gene activity. Chromatin immuno-precipitation assays demonstrated that a number of proteins representative for 1alpha,25(OH)2D3-mediated gene activation, such as VDR, RXR and RNA polymerase II, displayed a 1alpha,25(OH)2D3-dependent association with a region of the proximal PPARdelta promoter that contained the putative DR3-type VDRE. This was also true for other proteins that are involved in or are the subject of chromatin modification, such as the histone acetyltransferase CBP and histone 4, which displayed ligand-dependent association and acetylation, respectively. Finally, real-time PCR analysis demonstrated that 1alpha,25(OH)2D3 and the synthetic PPARdelta ligand L783483 show a cell and time-dependent interference in each other's effects on VDR mRNA expression, so that their combined application shows complex effects on the induction of VDR target genes, such as CYP24. Taken together, we conclude that PPARdelta is a primary 1alpha,25(OH)2D3-responding gene and that VDR and PPARdelta signaling pathways are interconnected at the level of cross-regulation of their respective transcription factor mRNA levels.
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PMID:The human peroxisome proliferator-activated receptor delta gene is a primary target of 1alpha,25-dihydroxyvitamin D3 and its nuclear receptor. 1589 Jan 93

In a search for improved therapies for prostate cancer, we investigated the effect of genistein in combination with 1alpha-25-dihydroxyvitamin D3 [1,25(OH)2D3], on the growth of DU145 human prostate cancer cells. DU145 cells were very resistant to the growth inhibitory action of 1,25(OH)2D3 or genistein when administered individually. However, the combination caused a significant growth inhibition seen at lower concentrations of both agents. 1,25(OH)2D3 induces the expression of the CYP24 gene, which codes for the enzyme that initiates the catabolism of 1,25(OH)2D3. We showed for the first time that genistein at low doses (50-100 nM) directly inhibited CYP24 at the enzyme level. Addition of genistein to mitochondrial preparations inhibited CYP24 enzyme activity in a noncompetitive manner. CYP24 inhibition by genistein increased the half-life of 1,25(OH)2D3 thereby augmenting the homologous up-regulation of the vitamin D receptor (VDR) both at the mRNA and protein levels. Genistein co-treatment enhanced 1,25(OH)2D3-mediated transactivation of the vitamin D responsive reporters OC-Luc and OP-Luc transfected into DU145 cells. Consistent with the growth inhibition due to the combination treatment, significant changes in the expression of genes involved in growth arrest and apoptosis were seen. We conclude that genistein potentiates the antiproliferative actions of 1,25(OH)2D3 in DU145 cells by two mechanisms: (i) an increase in the half-life of 1,25(OH)2D3 due to the direct inhibition of CYP24 enzyme activity and (ii) an amplification of the homologous up-regulation of VDR. Together these two effects lead to a substantial enhancement of the cellular responses to the growth inhibitory and pro-apoptotic signaling by 1,25(OH)2D3.
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PMID:Genistein potentiates the growth inhibitory effects of 1,25-dihydroxyvitamin D3 in DU145 human prostate cancer cells: role of the direct inhibition of CYP24 enzyme activity. 1595 19

Substantial experimental evidence indicates that the hormonal form of vitamin D promotes the differentiation and inhibits the proliferation, invasiveness, and metastasis of human prostatic cancer cells. Results from epidemiologic studies of vitamin D status and/or vitamin D receptor (VDR) polymorphisms and prostate cancer risk have been mixed. We conducted a population-based, case-control study of advanced prostate cancer among men ages 40 to 79 years from the San Francisco Bay area. Interview data on lifetime sun exposure and other risk factors were collected for 905 non-Hispanic White men (450 cases and 455 controls). Using a reflectometer, we measured constitutive skin pigmentation on the upper underarm (a sun-protected site) and facultative pigmentation on the forehead (a sun-exposed site) and calculated a sun exposure index from these measurements. Biospecimens were collected for 426 cases and 440 controls. Genotyping was done for VDR polymorphisms in the 5' regulatory region (Cdx-2), exon 2 (FokI), and the 3' region (TaqI and BglI). Reduced risk of advanced prostate cancer was associated with high sun exposure determined by reflectometry [odds ratio (OR), 0.51; 95% confidence interval (95% CI), 0.33-0.80] and high occupational outdoor activity (OR, 0.73; 95% CI, 0.48-1.11). Significant risk reductions with the high-activity alleles FokI FF or Ff, TaqI tt, and BglI BB genotypes and a nonsignificant reduction with Cdx-2 AG or AA genotype were observed in the presence of high sun exposure, with ORs ranging from 0.46 to 0.67. Our findings support the hypothesis that sun exposure and VDR polymorphisms together play important roles in the etiology of prostate cancer.
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PMID:Sun exposure, vitamin D receptor gene polymorphisms, and risk of advanced prostate cancer. 1595 97

The vitamin-D endocrine system is involved in a wide variety of biological processes including bone metabolism, modulation of immune responses, and regulation of cell proliferation and differentiation. Variation in this endocrine system have, thus, been linked to several common diseases, including osteoarthritis (OA), diabetes, cancer, cardiovascular ailments, urolithiasis and tuberculosis. Activity of Vit-D is mediated by the vitamin D receptor (VDR), a ligand dependent receptor. VDR gene polymorphisms thus represent strong positional candidates for different diseases like prostate cancer, urolithiasis, inflammatory bowl disease and osteoporosis. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and can reveal modest and subtle but true biological effects. The abundance of polymorphisms in the human genome as well as high frequencies in human populations have made them targets to explain variation in risk of common diseases. The present study was carried out to determine the distribution of VDR gene (Fok-I, Taq-I and Apa-I) polymorphisms using a PCR-based restriction analysis in unrelated normal healthy individuals from a north Indian population. We obtained allelic frequencies of (68.5% vs 31.5%), (66% vs 34%) and (58% vs 42%) for (F vs f), (T vs t) and (A vs a) alleles, with 44%, 49% and 7%, respectively, for genotypes FF, Ff and ff , 49%, 40% and 11% for TT, Tt and tt and 36%, 44% and 20% for AA, Aa and aa. Our results suggest that the frequency and distribution of the polymorphisms in India are substantially different from in other populations and ethnic groups. Thus the data signify an impact of ethnicity and provide a basis for future epidemiological and clinical studies.
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PMID:Vitamin-D receptor (VDR) gene (Fok-I, Taq-I and Apa-I) polymorphisms in healthy individuals from north Indian population. 1610 24

In this study, we further investigated the mechanisms by which pseudophosphorylated prolactin (S179D PRL) inhibits the growth of human prostate cancer cells. When treated with S179D PRL for 3 days, LnCAP cells responded by increasing expression of the vitamin D receptor (VDR) and the cell cycle regulatory molecule, p21, whereas PC3 and DU145 cells did not. After 5 days of treatment, both PC3 and DU145 cells responded. Untreated LnCAP cells express the short 1b form (SF1b) of the human prolactin receptor, but DU145 and PC3 cells express only low amounts of this receptor until elevated by treatment with S179D PRL. DU145 and PC3 cells become sensitive to the negative effects of S179D PRL on cell number after induction of the SF1b. Transfection of either SF1b or SF1a into PC3 or DU145 cells made them sensitive to S179D PRL in the 3-day time frame, a finding that was not duplicated by transfection with the long form of the receptor. Treatment of LnCAP cells with S179D PRL increased long-term activation of extracellular signal-regulated kinase 1/2 (ERK1/2). This did not occur in PC3 and DU145 cells until transfection with SF1a/SF1b. Blockade of ERK signaling eliminated S179D PRL-stimulated expression of the VDR and p21 in LnCAP cells and transfected PC3 and DU145 cells. We conclude that initiation of alternative splicing to produce SF1b, and subsequent altered signaling, contribute to the growth inhibitory mechanisms of S179D PRL. This is the first indication of a role for short prolactin receptors in the regulation of cell proliferation.
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PMID:S179D prolactin increases vitamin D receptor and p21 through up-regulation of short 1b prolactin receptor in human prostate cancer cells. 1610 6

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