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)

The function and distribution of alpha1-adrenergic receptor (AR) subtypes in prostate cancer cells is well characterized. Previous studies have used RNA localization or low-avidity antibodies in tissue or cell lines to determine the alpha1-AR subtype and suggested that the alpha1A-AR is dominant. Two androgen-insensitive, human metastatic cancer cell lines DU145 and PC3 were used as well as the mouse TRAMP C1-C3 primary and clonal cell lines. The density of alpha1-ARs was determined by saturation binding and the distribution of the different alpha1-AR subtypes was examined by competition-binding experiments. In contrast to previous studies, the major alpha1-AR subtype in DU145, PC3 and all of the TRAMP cell lines is the alpha1B-AR. DU145 cells contained 100% of the alpha1B-AR subtype, whereas PC3 cells were composed of 21% alpha1 A-AR and 79% alpha1B-AR. TRAMP cell lines contained between 66% and 79% of the alpha1B-AR with minor fractions of the other two subtypes. Faster doubling time in the TRAMP cell lines correlated with decreasing alpha 1B-AR and increasing alpha1 A- and alpha1D-AR densities. Transfection with EGFP-tagged alpha1B-ARs revealed that localization was mainly intracellular, but the majority of the receptors translocated to the cell surface after extended preincubation (18 hr) with either agonist or antagonist. Localization was confirmed by ligand-binding studies and inositol phosphate assays where prolonged preincubation with either agonist and/or antagonist increased the density and function of alpha 1-ARs, suggesting that the native receptors were mostly intracellular and nonfunctional. Our studies indicate that alpha1B-ARs are the major alpha1-AR subtype expressed in DU145, PC3, and all TRAMP cell lines, but most of the receptor is localized in intracellular compartments in a nonfunctional state, which can be rescued upon prolonged incubation with any ligand.
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PMID:Dominance of the alpha1B-adrenergic receptor and its subcellular localization in human and TRAMP prostate cancer cell lines. 1736 8

Inflammation enhances tumour promotion through NF-kappaB-dependent mechanisms. NF-kappaB was also proposed to promote metastatogenesis through epithelial-mesenchymal transition. Yet a mechanistic link between inflammation and metastasis is missing. We identified a role for IkappaB kinase alpha (IKKalpha), activated by receptor activator of NF-kappaB (RANK/TNFRSF11A), in mammary epithelial proliferation during pregnancy. Owing to similarities between mammary and prostate epithelia, we examined IKKalpha involvement in prostate cancer and its progression. Here we show that a mutation that prevents IKKalpha activation slows down CaP growth and inhibits metastatogenesis in TRAMP mice, which express SV40 T antigen in the prostate epithelium. Decreased metastasis correlated with elevated expression of the metastasis suppressor Maspin, the ablation of which restored metastatic activity. IKKalpha activation by RANK ligand (RANKL/TNFSF11) inhibits Maspin expression in prostate epithelial cells, whereas repression of Maspin transcription requires nuclear translocation of active IKKalpha. The amount of active nuclear IKKalpha in mouse and human prostate cancer correlates with metastatic progression, reduced Maspin expression and infiltration of prostate tumours with RANKL-expressing inflammatory cells. We propose that tumour-infiltrating RANKL-expressing cells lead to nuclear IKKalpha activation and inhibition of Maspin transcription, thereby promoting the metastatic phenotype.
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PMID:Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. 1737 33

Prostate cancer (CaP) is a fast-growing health and social problem already representing the second leading cause of cancer-related death among men in Western countries. Lifestyle-related factors and diet are major contributors for CaP promotion. Because of unfavourable prognosis of extra-prostatic CaP, prevention is considered the best approach to fight it at present time. Green Tea Catechins (GTCs) were proven effective at inhibiting cancer growth in several laboratory studies. We recently performed a pilot clinical trial in HG-PIN subjects showing that only 1/30 tumour was diagnosed in subjects treated for 1 year with 600 mg/die GTCs, while 9/30 cancers were found in placebo-treated men. CaP is an elusive disease, whose biological behaviour is difficult to predict. We have recently described and validated a RT-qPCR method based on a 8-genes signature that significantly discriminated benign tissue from CaP in both humans and TRAMP mice spontaneously developing CaP. In the animal model, also GTCs-resistant CaP was significantly discriminated from GTCs-sensitive CaP, i.e. responding to GTCs administration. Preliminary experiments in our laboratory have shown that this method can be successfully applied to a single tissue needle biopsy specimen in humans. The combination of these results may be of particular significance on the field. In fact, GTCs treatment for men at high risk of CaP as first line prevention therapy in combination with the 8-genes signature profiling in tissue needle biopsies for real time monitoring of patient's response might importantly change, in the near future, the clinical managing of this highly diffuse malignancy.
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PMID:Clinical relevance of the inhibitory effect of green tea catechins (GtCs) on prostate cancer progression in combination with molecular profiling of catechin-resistant tumors: an integrated view. 1738 27

Anti-proliferative properties of genistein in prostate and other cancers have been studied extensively. However, the identification of genistein targets that may mediate its chemopreventive effects in vivo requires further elucidation. In this study, we have demonstrated that the incorporation of genistein in the diet of transgenic adenocarcinoma mouse prostate model (TRAMP/FVB) mice resulted in a reduction in prostate size and the incidence of poorly differentiated (PD) cancer ensuing in an accumulation of prostates at the prostatic intra-epithelial neoplasia (PIN) stage. TRAMP/FVB prostate cancer progression and the onset of PD cancer were characterized by the activation of acutely transforming retrovirus AKT8 in rodent T cell lymphoma (Akt), phosphorylation of glycogen synthase kinase 3-beta (GSK-3beta), post-transcriptional up-regulation of cyclin D1 and repression of cadherin-1 via snail-1 up-regulation. Incorporation of genistein in the diet significantly inhibited the activation of Akt, restored the activation of GSK-3beta, reduced cyclin D1 levels post-transcriptionally and maintained the expression of the cadherin-1 complex via down-regulation of snail-1. By identifying the Akt-GSK-3 pathway and subsequently its downstream effectors, as targets for genistein chemopreventive action, we have elucidated one possible mechanism by which genistein decreases the proliferative potential, retards cancer progression and maintains the integrity of the prostatic epithelial cells in vivo.
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PMID:Akt GSK-3 pathway as a target in genistein-induced inhibition of TRAMP prostate cancer progression toward a poorly differentiated phenotype. 1746 12

Dendritic cells (DCs) are highly potent initiators of the immune response, but DC effector functions are often inhibited by immunosuppressants such as transforming growth factor beta (TGF-beta). The present study was conducted to develop a treatment strategy for prostate cancer using a TGF-beta-insensitive DC vaccine. Tumor lysate-pulsed DCs were rendered TGF-beta insensitive by dominant-negative TGF-beta type II receptor (TbetaRIIDN), leading to the blockade of TGF-beta signals to members of the Smad family, which are the principal cytoplasmic intermediates involved in the transduction of signals from TGF-beta receptors to the nucleus. Expression of TbetaRIIDN did not affect the phenotype of transduced DCs. Phosphorylated Smad-2 was undetectable and expression of surface co-stimulatory molecules (CD80/CD86) were upregulated in TbetaRIIDN DCs after antigen and TGF-beta1 stimulation. Vaccination of C57BL/6 tumor-bearing mice with the TbetaRIIDN DC vaccine induced potent tumor-specific cytotoxic T lymphocyte responses against TRAMP-C2 tumors, increased serum IFN-gamma and IL-12 level, inhibited tumor growth and increased mouse survival. Furthermore, complete tumor regression occurred in two vaccinated mice. These results demonstrate that blocking TGF-beta signals in DC enhances the efficacy of DC-based vaccines.
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PMID:TGF-beta insensitive dendritic cells: an efficient vaccine for murine prostate cancer. 1747 21

Safingol [(2S,3S)-2-amino-1,3-octadecanediol] is an unnatural l-threo-stereoisomer of sphinganine that is cytotoxic for cancer cells in culture and is being tested in phase 1 human clinical trials. To determine if safingol can be absorbed orally and if it affects prostate cancer in a mouse strain used in prostate cancer studies, safingol was fed to TRAMP (transgenic adenocarcinoma of mouse prostate) mice for 2 weeks at 0.0125% to 0.1% w/w of the diet. Analysis of safingol and safingol metabolites in blood and tissues by liquid chromatography electrospray ionization tandem mass spectrometry revealed uptake in tissue and extensive conversion of safingol to N-acyl species (comparable to natural "ceramides") and mono-, di-, and tri-N-methyl metabolites that have not been observed previously. Safingol caused significant hepatotoxicity at all dosages, as reflected in elevated liver alanine aminotransferase, and at the highest dose (0.1 %) caused changes in liver histology (appearance of autophagosomal vacuoles) and renal toxicity (based on elevation of blood urea nitrogen) and decreases in packed blood cell volume and body weight. Safingol did not inhibit the prostate pre-neoplastic lesion (prostate intraepithelial neoplasia) in TRAMP mice; however, additional studies at lower dosages for longer time were not pursued due to host toxicity. Safingol and its N-methyl metabolites were cytotoxic to both a human prostate cell line (DU145) and mouse BALB 3T3 cells; therefore, the host and potential antitumor toxicity may be due to multiple molecular species of safingol.
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PMID:Safingol toxicology after oral administration to TRAMP mice: demonstration of safingol uptake and metabolism by N-acylation and N-methylation. 1761 6

Evidence suggests that the histone deacetylase, SIRT1, is a mediator of life span extension by calorie restriction; however, SIRT1 may paradoxically increase the risk of cancer. To better understand the relationship among SIRT1, energy balance, and cancer, two experiments were done. First, a transgenic mouse model of prostate cancer (transgenic adenocarcinoma of mouse prostate; TRAMP) was used to determine the role of energy balance on SIRT1 expression and the effect of cancer stage on SIRT1 and hypermethylated in cancer-1 (HIC-1). Second, immunohistochemistry was done on human prostate tumors to determine if SIRT1 was differentially expressed in tumor cells versus uninvolved cells. Results show that SIRT1 is not increased in the dorsolateral prostate (DLP) of calorie-restricted mice during carcinogenesis. In contrast, when examined in the DLP as a function of pathologic score, SIRT1 was significantly elevated in mice with poorly differentiated adenocarcinomas compared with those with less-advanced disease. HIC-1, which has been shown to regulate SIRT1 levels, was markedly reduced in the same tumors, suggesting that a reduction in HIC-1 may be in part responsible for the increased expression of SIRT1 in prostatic adenocarcinomas. Furthermore, immunostaining of human prostate tumors showed that cancer cells had greater SIRT1 expression than uninvolved cells. In conclusion, DLP SIRT1 expression from calorie-restricted mice was not altered during carcinogenesis. However, SIRT1 expression was increased in mice with poorly differentiated adenocarcinomas and in human prostate cancer cells. Because SIRT1 may function as a tumor promoter, these results suggest that SIRT1 should be considered as a potential therapeutic target for prostate cancer.
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PMID:SIRT1 is significantly elevated in mouse and human prostate cancer. 1763 71

Deregulation of beta-catenin signaling is an important event in the genesis of several human malignancies including prostate cancer. We investigated the effects of apigenin, a naturally occurring plant flavone, on prostate carcinogenesis in TRAMP mice and further elucidated its mechanism of action. Oral intake of apigenin by gavage at doses of 20 and 50 microg/mouse/d, 6 days per week for 20 weeks, significantly decreased tumor volumes of the prostate as well as completely abolished distant-site metastases to lymph nodes, lungs, and liver in TRAMP mice. Apigenin-treated mice had significantly diminished weights of their genitourinary apparatuses and dorsolateral and ventral prostate lobes, compared with the control group, and showed reduced proliferation and increased apoptosis in the dorsolateral prostates, which correlated with elevated plasma apigenin levels. Continuous intake of apigenin up to 50 weeks by TRAMP mice significantly improved their overall survival. P.o. administration of apigenin further resulted in increased levels of E-cadherin and decreased levels of nuclear beta-catenin, c-Myc, and cyclin D1 in the dorsolateral prostates of TRAMP mice. Similar effects were noted in TRAMP mice with established tumors. Treatment of DU145 human prostate cancer cells with 10 and 20 micromol/L apigenin also increased protein levels of E-cadherin by 27% to 74%, inhibited nuclear translocation of beta-catenin and its retention in the cytoplasm, and decreased c-Myc and cyclin D1 levels, an effect similar to the exposure of cells to beta-catenin small interfering RNA. Our results indicate that apigenin effectively suppressed prostate carcinogenesis in TRAMP mice, at least in part, by blocking beta-catenin signaling.
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PMID:Blockade of beta-catenin signaling by plant flavonoid apigenin suppresses prostate carcinogenesis in TRAMP mice. 1763 4

The nitroreductase (NR)/CB1954 enzyme prodrug system has given promising results in pre-clinical studies and is currently being assessed in phase I and II clinical trials in prostate cancer. Enhanced cell killing by apparent immune-mediated mechanisms has been shown in pancreatic and colorectal cancer models, by co-expressing murine granulocyte macrophage colony-stimulating factor (GM-CSF) with NR in a single replication deficient adenoviral vector. This consists of the CMV immediate early promotor driving expression of NR, with an internal ribosome entry site (IRES) and the gene for murine GM-CSF (mGM-CSF). To examine if similar enhancement of tumour cell killing could be produced in prostate cancer, the TRAMP model was chosen. Results illustrate that the combination of suicide gene therapy using NR and CB1954, with cytokine stimulation with mGM-CSF gives an improved response compared with either modality alone. The mechanism of this improved response is however likely to be non-immune based as it lacks a memory effect.
Prostate Cancer Prostatic Dis 2008
PMID:Combining gene and immunotherapy for prostate cancer. 1772 52

Prostate cancer is the second leading cause of cancer-related deaths in men. Fatty acid synthase (FASN) is normally upregulated during human prostate cancer onset and metastatic progression and its expression positively correlates with the development of advanced metastatic disease. However, it remains unknown what molecular factor(s) control FASN expression. It has been hypothesized that FASN functions as a tumor promoter during prostate cancer progression in humans. Consistently, an established mouse of model of prostate cancer, termed TRAMP mice, also shows the progressive upregulation of FASN levels during prostate cancer development. Here, we examine the role of caveolin-1 (Cav-1) in regulating FASN expression during prostate cancer progression. For this purpose, we crossed Cav-1-/- null mice with TRAMP mice to generate TRAMP/Cav-1+/+ and TRAMP/Cav-1-/- mice. Then, we assessed the expression of FASN in Cav-1+/+ and Cav-1-/- prostate tumors by immuno-histochemistry and Western blot analysis. Interestingly, our results indicate that FASN fails to be upregulated in Cav-1-/- tumors. Importantly, the tumors examined were the same morphological grade, but Cav-1-/- tumors were dramatically smaller and did not metastasize efficiently. We conclude that Cav-1 expression is normally required for the upregulation of FASN during prostate cancer progression. These results also mechanistically explain why TRAMP/Cav-1-/- mice are dramatically resistant to the development of prostate tumors and lung metastases, as they lack the expression of the FASN tumor promoter. Thus, TRAMP/Cav-1-/- mice will provide a novel model system to elucidate the role of FASN in prostate tumor progression. In addition, our results provide the first molecular genetic evidence that Cav-1 functions upstream of FASN during prostate cancer progression.
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PMID:Caveolin-1 is required for the upregulation of fatty acid synthase (FASN), a tumor promoter, during prostate cancer progression. 1778 30


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