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 involvement of Nrf2-a bZip transcription factor in soy isoflavones induced protection against oxidative stress and cancer has been reported. To gain better insight into the role of Nrf2 in prostate cancer chemoprevention by soy isoflavones, we examined the pharmacogenomics and gene expression profiles elicited by soy isoflavones in the prostates of C57BL/6J/Nrf2(-/-) and C57BL6J/Nrf2(+/+) wildtype. The profiles were analyzed using 45000 Affymetrix mouse genome 430-2.0 array and Genespring-7.2 software. The results obtained from microarray were further validated by real-time reverse transcription-PCR. Clusters of genes that were induced or suppressed more than twofold were identified as Nrf2 regulated soy isoflavone induced or suppressed genes. Classification based on their biological function revealed that genes mainly belonging to the categories of electron transport, phase II metabolizing enzymes, cell growth and differentiation, apoptosis, cell cycle, transcription factors, transport, mRNA processing, and carbohydrate homeostasis were either induced or suppressed by soy isoflavone and regulated by Nrf2. In addition, modulation of novel target genes such as LATS2 and GREB1 were identified to be mediated by Nrf2. Thus our current study provides a potential link between cancer chemopreventive properties of soy derived phytochemicals, the transcription factor Nrf2 and prevention of prostate cancer.
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PMID:Pharmacogenomic profile of soy isoflavone concentrate in the prostate of Nrf2 deficient and wild-type mice. 1823 73

The impact of oxidative stress in human cancer has been extensively studied. It is accepted that elevated reactive oxygen species (ROS) promote mutagenic DNA damage. Even with an extensive armament of cellular antioxidants and detoxification enzymes, alterations to DNA occur that initiate cellular transformation. Erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) is a basic-region leucine zipper transcription factor that mediates the expression of key protective enzymes through the antioxidant-response element (ARE). By analysing 10 human prostate cancer microarray data sets, we have determined that Nrf2 and members of the glutathione-S-transferase (GST) mu family are extensively decreased in human prostate cancer. Using the TRAMP transgene and Rb and Nrf2 knockout murine models, we demonstrated that the loss of Nrf2 initiates a detrimental cascade of reduced GST expression, elevated ROS levels and ultimately DNA damage associated with tumorigenesis. Based on overwhelming data from clinical samples and the current functional analysis, we propose that the disruption of the Nrf2-antioxidant axis leads to increased oxidative stress and DNA damage in the initiation of cellular transformation in the prostate gland.
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PMID:The role of Nrf2 in increased reactive oxygen species and DNA damage in prostate tumorigenesis. 1837 16

Gamma-tocopherol (gamma-T) alone or in combination with alpha-tocopherol has been shown to suppress biomarkers of oxidative stress in asthamatics and human subjects with metabolic syndrome. Oxidative stress has been implicated as a key event in prostate carcinogenesis. Hence, the purpose of this study was to examine the effects of gamma-tocopherol-enriched mixed tocopherol diet on prostate carcinogenesis in a murine prostate cancer model (TRAMP). 8 week old TRAMP males were fed 0.1% gamma-T-enriched mixed tocopherol diet that contained 20-fold higher levels of gamma-tocopherol, and roughly 3-fold higher levels of alpha-tocopherol. The effect of such diet on tumor and PIN development was observed. The expression of phase II detoxifying, antioxidant enzymes and Nrf2 mRNA and protein were determined by RT-PCR, immunohistochemistry and western blotting techniques. Treatment with gamma-T-enriched mixed tocopherols significantly suppressed the incidence of palpable tumor and Prostate Intraepithelial Neoplasia (PIN) development without affecting the expression of the transgene (SV-40). Tumor progression occurred with a significant suppression of antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase, heme-oxygenase-1 and phase II detoxifying enzymes. Treatment with gamma-T-enriched mixed tocopherol diet upregulated the expression of most detoxifying and antioxidant enzymes. Nrf2-a redox sensitive transcription factor known to mediate the expression of phase II detoxifying enzymes, was also significantly upregulated following treatment with gamma-T-enriched mixed tocopherol diet. Gamma-T-enriched mixed tocopherols significantly up-regulated the expression of Nrf2 and its related detoxifying and antioxidant enzymes thereby suppressing PIN and tumor development.
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PMID:Gamma-tocopherol-enriched mixed tocopherol diet inhibits prostate carcinogenesis in TRAMP mice. 1911 3

FGFR2 gene at human chromosome 10q26 encodes FGFR2b and FGFR2c isoforms functioning as FGF receptors with distinct expression domain and ligand specificity. FGFR2 plays oncogenic and anti-oncogenic roles in a context-dependent manner. Single nucleotide polymorphisms (SNPs) within intron 2 of FGFR2 gene are associated with breast cancer through allelic FGFR2 upregulation. Missense mutations or copy number gains of FGFR2 gene occur in breast cancer and gastric cancer to activate FGFR2 signaling. Aberrant FGFR2 signaling activation induces proliferation and survival of tumor cells. The class switch from FGFR2b to FGFR2c occurs during progression of prostate cancer and bladder cancer because of spliceosome dysregulation. In addition, epidermal Fgfr2b knockout mice show increased sensitivity to chemical carcinogenesis partly due to the failure of Nfe2l2 (Nrf2)-mediated detoxification of reactive oxygen species (ROS). Loss of FGFR2b signaling induces epithelial-to-mesenchymal transition (EMT) and unruly ROS. FGFR2 signaling dysregulation due to the accumulation of epigenetic modifications and genetic alterations during chronic inflammation, smoking, increased caloric uptake, and decreased exercise leads to carcinogenesis. PD173074, SU5402, AZD2171, and Ki23057 are small-molecule FGFR inhibitors. Human antibody, peptide mimetic, RNA aptamer, siRNA, and synthetic microRNA (miRNA) are emerging technologies to be applied for cancer therapeutics targeted to FGFR2. Because novel sequence technology and peta-scale super-computer are opening up the sequence era following the genome era, personalized medicine prescribing targeted drugs based on germline and/or somatic genomic information is coming reality. Application of FGFR2 inhibitors for cancer treatment in patients with FGFR2 mutation or gene amplification is beneficial; however, that for cancer prevention in people with FGFR2 risk allele might be disadvantageous due to the impediment of a cytoprotective mechanism against oxidative stress.
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PMID:FGFR2-related pathogenesis and FGFR2-targeted therapeutics (Review). 1921 47

Induction of phase II detoxifying enzymes is a major cellular strategy for reducing the risk of cancer. We previously reported that carotenoids activate the electrophile/antioxidant response element (EpRE/ARE) transcription system and induced the expression of phase II enzymes. Various electrophilic phytonutrients have been shown to induce the EpRE/ARE system by disrupting the inhibitory activity of Keap1 on Nrf2, the major EpRE/ARE activating transcription factor. However, hydrophobic carotenoids such as lycopene lack any electrophilic group and, thus, are unlikely to directly activate Nrf2 and the EpRE/ARE system. Here we demonstrate that carotenoid oxidation products are the active mediators in the stimulation of the EpRE/ARE system by carotenoids. Two lines of evidence support this conclusion. (A) The oxidized derivatives, extracted by ethanol from partially oxidized lycopene, transactivated EpRE/ARE with a potency similar to that of the unextracted lycopene mixture, whereas the intact carotenoid showed a nonsignificant effect. (B) Using a series of characterized mono- and diapocarotenoids that potentially can be derived from in vivo metabolism of carotenoids we defined the following structure-activity rules for activation of EpRE/ARE: (I) aldehydes and not acids are the active molecules; (II) the activity depends on the relative position of the methyl group to the terminal aldehyde which determines the reactivity of the conjugated double bond; (III) the optimal length of a dialdehyde derivative is 12 carbons in the main chain of the molecule. The apocarotenals inhibited breast and prostate cancer cell growth with a similar order of potency to the activation of EpRE/ARE. These results may provide a mechanistic explanation for the cancer preventive activity of carotenoids.
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PMID:Structure activity relationship of carotenoid derivatives in activation of the electrophile/antioxidant response element transcription system. 1952 36

ATP-binding cassette, subfamily G, member 2 (ABCG2) is expressed in both normal and cancer cells and plays a crucial role in side population (SP) formation and efflux of xenobiotics and drugs. Nrf2, a redox-sensing transcription factor, on constitutive activation in non-small-cell lung cancer cells upregulates a wide spectrum of genes involved in redox balance, glutathione metabolism, and drug detoxification, which contribute to chemoresistance and tumorigenicity. This study examined the mechanism underlying Nrf2-dependent expression of ABCG2 and its role in the multidrug resistance phenotype. In silico analysis of the 5'-promoter flanking region of ABCG2 identified an antioxidant response element (ARE) at -431 to -420 bp. A detailed promoter analysis using luciferase reporter assays showed that ARE at -431 to -420 bp is critical for the Nrf2-mediated expression in lung cancer cells. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays revealed that Nrf2 interacts with the ABCG2 ARE element at -431 to -420 bp in vitro and in vivo. Disruption of Nrf2 expression in lung and prostate cancer cells, by short hairpin RNA, attenuated the expression of ABCG2 transcript and protein, and dramatically reduced the SP fraction in Nrf2-depleted cancer cells. Moreover, depleted levels of ABCG2 in these Nrf2 knockdown cells sensitized them to mitoxantrone and topotecan, two chemotherapy drugs detoxified mainly by ABCG2. As expected, overexpression of Nrf2 cDNA in lung epithelial cells led to an increase in ABCG2 expression and a 2-fold higher SP fraction. Thus, Nrf2-mediated regulation of ABCG2 expression maintains the SP fraction and confers chemoresistance.
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PMID:Expression of ABCG2 (BCRP) is regulated by Nrf2 in cancer cells that confers side population and chemoresistance phenotype. 2068 44

Oxidative stress, implicated in the etiology of cancer, results from an imbalance in the production of reactive oxygen species (ROS) and cell's own antioxidant defenses. ROS deregulate the redox homeostasis and promote tumor formation by initiating an aberrant induction of signaling networks that cause tumorigenesis. Ultraviolet (UV) exposures, gamma-radiation and other environmental carcinogens generate ROS in the cells, which can exert apoptosis in the tumors, thereby killing the malignant cells or induce the progression of the cancer growth by blocking cellular defense system. Cancer stem cells take the advantage of the aberrant redox system and spontaneously proliferate. Oxidative stress and gene-environment interactions play a significant role in the development of breast, prostate, pancreatic and colon cancer. Prolonged lifetime exposure to estrogen is associated with several kinds of DNA damage. Oxidative stress and estrogen receptor-associated proliferative changes are suggested to play important roles in estrogen-induced breast carcinogenesis. BRCA1, a tumor suppressor against hormone responsive cancers such as breast and prostate cancer, plays a significant role in inhibiting ROS and estrogen mediated DNA damage; thereby regulate the redox homeostasis of the cells. Several transcription factors and tumor suppressors are involved during stress response such as Nrf2, NF-kappaB and BRCA1. A promising strategy for targeting redox status of the cells is to use readily available natural substances from vegetables, fruits, herbs and spices. Many of the phytochemicals have already been identified to have chemopreventive potential, capable of intervening in carcinogenesis.
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PMID:Redox regulation in cancer: a double-edged sword with therapeutic potential. 2071 25

The process of cancer development consists of three sequential stages termed initiation, promotion, and progression. Oxidative stress damages DNA and introduces mutations into oncogenes or tumor suppressor genes, thus contributing to cancer development. Cancer chemoprevention is defined to prevent or delay the development of cancer by the use of natural or synthetic substances. In the present study, we synthesized a series of organoselenium compounds and evaluated their possible chemopreventive properties in human prostate cancer LNCaP cells. Among 42 organoselenium compounds tested, two compounds, 3-selena-1-dethiacephem 13 and 3-selena-1-dethiacephem 14 strongly activated the Nrf2/ARE (antioxidant response element) signaling and thus markedly increased expression of heme oxygenase-1 (HO-1), a phase II antioxidant enzyme. Translocation of Nrf2 to the nucleus preceded HO-1 protein induction by two compounds. The intracellular ROS level was strongly reduced immediately after treatment with these compounds, showing that they are potent antioxidants. Finally, both compounds inhibited cell growth via cell cycle arrest. Our findings suggest that compounds 13 and 14 could not only attenuate oxidative stress through Nrf2/ARE activation and direct ROS scavenging but also inhibit cell growth. Thus, these compounds possess the potential as pharmacological agents for chemoprevention of human prostate cancer.
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PMID:Identification of organoselenium compounds that possess chemopreventive properties in human prostate cancer LNCaP cells. 2080 33

Prostate cancer (PCa) is one of the most deadly malignancies among men in the United States. Although localized prostate cancer can be effectively treated via surgery or radiation, metastatic disease is usually lethal. Recent evidence suggests that the development and progression of human prostate cancer involves complex interplay between epigenetic alterations and genetic defects. We have recently demonstrated that Nrf2, a master regulator of cellular antioxidant defense systems, was epigenetically silenced during the progression of prostate tumorigenesis in TRAMP mice. The aim of this study is to investigate the potential of curcumin (CUR), a dietary compound that we have reported to be able to prevent the development of prostate cancer in TRAMP mice, as a DNA hypomethylation agent. Using bisulfite genomic sequencing (BGS), treatment of TRAMP C1 cells we showed that CUR reversed the methylation status of the first 5 CpGs in the promoter region of the Nrf2 gene. Methylation DNA immunoprecipitation (MeDIP) analysis revealed that CUR significantly reduced the anti-mecyt antibody binding to the first 5 CpGs of the Nrf2 promoter, corroborated the BGS results. Demethylation of Nrf2 was found to be associated with the re-expression of Nrf2 and one of its downstream target gene, NQO-1, one of the major anti-oxidative stress enzymes, both at the mRNA and protein levels. Taken together, our current study suggests that CUR can elicit its prostate cancer chemopreventive effect, potentially at least in part, through epigenetic modification of the Nrf2 gene with its subsequent induction of the Nrf2-mediated anti-oxidative stress cellular defense pathway.
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PMID:Pharmacodynamics of curcumin as DNA hypomethylation agent in restoring the expression of Nrf2 via promoter CpGs demethylation. 2178 56

Growing evidence suggests epigenetic alteration is involved during the development and progression of prostate cancer. Previously, we found Nrf2, a key regulator of cellular antioxidant defense systems, was silenced through epigenetic mechanism during tumorigenesis in vivo TRAMP mice and in vitro TRAMP C1 cells. Sulforaphane (SFN) in cruciferous vegetable has been demonstrated to be a potent cancer prevention agent for years. The aim of this study is to investigate the potential of SFN to restore Nrf2 expression in TRAMP C1 cells through epigenetic modifications. Bisulfite genomic sequencing results indicated that SFN treatment led to demethylation of the first 5 CpGs in the promoter region of the Nrf2 gene in TRAMP C1 cells. Using methylation DNA immunoprecipitation (MeDIP) assay, SFN significantly reduced the ratio of anti-mecyt antibody binding to the Nrf2 promoter containing the first 5 CpGs. SFN increased mRNA and protein expressions of Nrf2 and Nrf2 downstream target gene NQO-1. In addition, SFN decreased the protein levels of DNMT1 and DNMT3a. SFN treatment also attenuated the protein expression levels of HDACs 1, 4, 5, and 7 while increased the level of active chromatin marker acetyl-Histone 3 (Ac-H3). SFN treatments also increased chromatin-immunoprecipitated DNA of Nrf2 gene promoter using anti-Ac-H3 antibody. Taken together, our current study shows that SFN regulates Nrf2's CpGs demethylation and reactivation in TRAMP C1 cells, suggesting SFN may exert its chemopreventive effect in part via epigenetic modifications of Nrf2 gene with subsequent induction of its downstream anti-oxidative stress pathway.
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PMID:Sulforaphane enhances Nrf2 expression in prostate cancer TRAMP C1 cells through epigenetic regulation. 2341 17


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