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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Electrophiles formed during metabolic activation of chemical carcinogens and reactive oxygen species generated from endogenous and exogenous sources play a significant role in carcinogenesis. Cancer chemoprevention by induction of phase 2 proteins to counteract the insults of these reactive intermediates has gained considerable attention. Nuclear factor E2 p45-related factor 2 (Nrf2), a bZIP transcription factor, plays a central role in the regulation (basal and or inducible expression) of phase 2 genes by binding to the "antioxidant response element" in their promoters. Identification of novel Nrf2-regulated genes is likely to provide insight into cellular defense systems against the toxicities of electrophiles and oxidants and may define effective targets for achieving cancer chemoprevention. Sulforaphane is a promising chemopreventive agent that exerts its effect by strong induction of phase 2 enzymes via activation of Nrf2. In the present study, a transcriptional profile of small intestine of wild-type (nrf2 +/+) and knock out (nrf2 -/-) mice treated with vehicle or sulforaphane (9 micromol/day for 1 week, p.o.) was generated using the Murine Genome U74Av2 oligonucleotide array (representing approximately 6000 well-characterized genes and nearly 6000 expressed sequence tags). Comparative analysis of gene expression changes between different treatment groups of wild-type and nrf2-deficient mice facilitated identification of numerous genes regulated by Nrf2 including previously reported Nrf2-regulated genes such as NAD(P)H:quinone reductase (NQO1), glutathione S-transferase (GST), gamma-glutamylcysteine synthetase (GCS), UDP-glucuronosyltransferases (UGT),epoxide hydrolase, as well as a number of new genes. Also identified were genes encoding for cellular NADPH regenerating enzymes (glucose 6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and malic enzyme), various xenobiotic metabolizing enzymes, antioxidants (glutathione peroxidase, glutathione reductase, ferritin, and haptaglobin), and biosynthetic enzymes of the glutathione and glucuronidation conjugation pathways. The data were validated by Northern blot analysis and enzyme assays of selected genes. This investigation expands the horizon of Nrf2-regulated genes, highlights the cross-talk between various metabolic pathways, and divulges the pivotal role played by Nrf2 in regulating cellular defenses against carcinogens and other toxins.
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PMID:Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. 1223 84

Occupational exposure to nickel compounds is associated with lung cancer risk; both genotoxic and epigenetic mechanisms have been proposed. For comprehensive examination of the acute effects of nickel(II) acetate on gene expression in cultured human peripheral lung epithelial HPL1D cells, microarray analyses were carried out with cDNA chips (approximately 8000 cDNAs). Cells were exposed for 24 h to nontoxic (50, 100, and 200 microM) or toxic (400, 800, and 1600 microM) nickel(II) concentrations. Cluster analysis was applied to the 868 genes with > or = 2-fold change at any concentration. Two main clusters showed marked up- or down-regulation at the highest, toxic concentrations. The data further subdivided into 10 highly cohesive clusters with high probability, and of these only 2 had the same response trend at low nontoxic as at high concentrations, an observation of clear relevance to the process of high- to low-dose extrapolation in risk assessment. There were 113 genes showing > or = 2-fold change at the three lower nontoxic concentrations, those most relevant to in vivo carcinogenesis. In addition to expected responses of metallothionein, ferritin, and heat-shock proteins, the results revealed for the first time changed expression of some potential cancer-related genes in response to low-dose Ni(II): RhoA, dyskerin, interferon regulatory factor 1, RAD21 homologue, and tumor protein, translationally controlled. Overall, most of the genes impacted by nontoxic concentrations of nickel(II) acetate related to gene transcription, protein synthesis and stability, cytoskeleton, signaling, metabolism, cell membrane, and extracellular matrix.
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PMID:Gene expression dose-response changes in microarrays after exposure of human peripheral lung epithelial cells to nickel(II). 1291 1

In vitro and in vivo studies have associated iron with both the initiation and promotional stages of carcinogenesis. We investigated whether iron was associated with colorectal cancer in a nested case-control study within the alpha-tocopherol, beta-carotene cancer prevention study cohort. Exposure was assessed at baseline, using a 276-item food frequency questionnaire and a fasting serum sample. The study included 130 colorectal cancer cases (73 colon cancers and 57 rectal cancers) and 260 controls. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Supplemental iron intake was only reported for 4 cases and 18 controls; therefore, we were unable to obtain meaningful results for this variable. Comparing the highest to the lowest quartiles, there was an inverse association between serum ferritin and colorectal cancer risk (OR = 0.4, 95% CI = 0.2-0.9) and a suggestion of an inverse association between dietary iron and colorectal cancer risk (OR = 0.4, 95% CI = 0.1-1.1). In addition, serum ferritin, serum iron and transferrin saturation were all inversely associated with colon cancer risk specifically (OR = 0.2, 95% CI = 0.1-0.7, p trend = 0.02; OR = 0.2, 95% CI = 0.1-0.9, p trend = 0.05; OR = 0.1, 95% CI = 0.02-0.5, p trend = 0.003, respectively), whereas serum unsaturated iron binding capacity was positively associated with colon cancer risk (OR = 4.7, 95% CI = 1.4-15.1, p trend = 0.009). In summary, we found a significant inverse association between several serum iron indices and colon cancer risk.
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PMID:Iron and colorectal cancer risk in the alpha-tocopherol, beta-carotene cancer prevention study. 1642 87

Several metals are carcinogenic but little is known about the mechanisms by which they cause cancer. A pathway that may contribute to metal ion induced carcinogenesis is by hypoxia signaling, which involves a disruption of cellular iron homeostasis by competition with iron transporters or iron-regulated enzymes. To examine the involvement of iron in the hypoxia signaling activity of these metal ions we investigated HIF-1alpha protein stabilization, IRP-1 activity, and ferritin protein levels in human lung carcinoma A459 cells exposed to various agents in serum- and iron-free salt-glucose medium (SGM) or in normal complete medium. We also studied the effects of excess exogenous iron on these responses induced by nickel ion exposure. Our results show the following: (1) SGM enhanced metals-induced HIF-1alpha stabilization and IRP-1 activation (e.g., nickel and cobalt ions). (2) If SGM was reconstituted with a slight excess level (25 microM of FeSO(4)) of iron, this enhancing ability was significantly decreased. (3) The effect of a high level of exogenous iron (500 microM of FeSO(4)) on metal-induced hypoxia and iron metabolism was highly dependent on the order of addition. If treatment with the Fe and metal ions was simultaneous (co-treatment), the effects of nickel ion exposure were overwhelmed, since the added Fe reversed HIF-1alpha stabilization, decreased IRP-1 activity, and increased ferritin level. Pre-treatment with iron was not able to reverse the responses caused by nickel ion exposure. These results imply that it is important to consider the available iron concentration and suitable exposure design when studying metal-induced hypoxia or metal-induced disruption of Fe homeostasis.
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PMID:Effect of metal ions on HIF-1alpha and Fe homeostasis in human A549 cells. 1687 34

Iron is essential for proliferation of normal and neoplastic cells. Cellular iron uptake, utilization and storage are regulated by transcriptional and post-transcriptional mechanisms. We hypothesized that the disruption of iron homeostasis may modulate the growth properties of cancer cells. To address this, we employed H1299 lung cancer cells engineered for tetracycline-inducible overexpression of the post-transcriptional regulator iron regulatory protein 1 (IRP1). The induction of IRP1 (wild-type or the constitutive IRP1(C437S) mutant) did not affect the proliferation of the cells in culture, and only modestly reduced their efficiency to form colonies in soft agar. However, IRP1 dramatically impaired the capacity of the cells to form solid tumor xenografts in nude mice. Tumors derived from IRP1-transfectants were <20% in size compared to those from parent cells. IRP1 coordinately controls the expression of transferrin receptor 1 (TfR1) and ferritin by binding to iron-responsive elements (IREs) within their mRNAs. Biochemical analysis revealed high expression of epitope-tagged IRP1 in tumor tissue, which was associated with a profound increase in IRE-binding activity. As expected, this response misregulated iron metabolism by increasing TfR1 levels. Surprisingly, IRP1 failed to suppress ferritin expression and did not affect the levels of the iron transporter ferroportin. Our results show that the overexpression of IRP1 is associated with an apparent tumor suppressor phenotype and provide a direct regulatory link between the IRE/IRP system and cancer.
Carcinogenesis 2007 Apr
PMID:Overexpression of iron regulatory protein 1 suppresses growth of tumor xenografts. 1712 13

At present, the molecular mechanisms of hepatocellular carcinogenesis are not well-understood, and hepatocellular carcinoma (HCC) stays one of the most frequent and high-risk metastatic visceral neoplasms worldwide. For the identification of tumor-relevant proteins, we analyzed microdissected cells from nontumorous liver tissue (n = 28) and tissue derived from hepatic tumor center (n = 25), as well as tumor margin (n = 23). We unequivocally identified 53 proteins from hepatic tumor tissues by peptide fingerprint mapping and SELDI mass spectrometry that were separated using two-dimensional gel electrophoresis. Among a number of signals that were detected as significantly different in the protein profiling analysis, we identified for the first time ferritin light subunit (FLS) and adenylate kinase 3 alpha-like 1 (AK3), showing decreased expressions in hepatic tumor, as well as biliverdin reductase B (BVRB) that was upregulated in HCC. The use of ProteinChip technology in combination with tissue microdissection gives insight of the complex changes occurring at the protein level in hepatocellular cancer associated with tumor development and progression and resulted in three new potential diagnostically useful markers.
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PMID:Identification of specific protein markers in microdissected hepatocellular carcinoma. 1720 74

Exposure to asbestos is a known etiological factor in malignant mesothelioma (MM). However, in vitro cell culture studies have provided paradoxical evidence that asbestos exposure to mesothelial cells causes cytotoxicity or apoptosis rather than malignant transformation. Although it has been shown that the iron associated with asbestos participates in the cell toxicity and probably MM pathogenesis via generation of reactive oxygen species (ROS), the molecular mechanisms largely remain unknown. Here, we demonstrate that ferritin heavy chain (FHC), a core subunit of iron-binding protein ferritin, works as an anti-apoptotic protein against toxic asbestos and oxidative stress in human mesothelial cells and MM cells. We found that FHC was induced in asbestos-exposed MeT-5A human mesothelial cells. The mesothelial cell line stably expressing FHC generated less amount of hydrogen peroxide (H2O2), one of the main ROS, after asbestos exposure and was more resistant to apoptosis induced by H2O2 compared with the cells transfected with the empty vector. Next, we investigated biological roles of FHC in human MM cell. We found that NCI-H2052, a human MM cell line, had a higher expression of endogenous FHC than MeT-5A and used the cell to address FHC function in MM. NCI-H2052 showed reduced H2O2 production and an apoptosis-resistant phenotype compared with MeT-5A. Suppression of the over-expressed FHC by using FHC small interfering RNA rendered the MM cells sensitive to apoptosis, suggesting the contribution of FHC to apoptosis resistance of the MM cells. Our findings highlight the potential role of FHC in the pathogenesis of asbestos-induced mesothelioma.
Carcinogenesis 2007 Sep
PMID:Potential role of ferritin heavy chain in oxidative stress and apoptosis in human mesothelial and mesothelioma cells: implications for asbestos-induced oncogenesis. 1743 31

Free iron is a pro-oxidant and can induce oxidative stress and DNA damage. The carcinogenicity of iron has been demonstrated in animal models, and epidemiologic studies have shown associations with several human cancers. However, a possible role of excess body iron stores or of elevated iron intake in breast carcinogenesis has received little attention epidemiologically. We propose that iron overload and the disruption of iron homeostasis with a resulting increase in free iron may contribute to the development of breast cancer, and we summarize the relevant evidence from mechanistic studies, animal experiments, and studies in humans. Over time a high intake of iron can lead to iron overload. Furthermore, body iron stores increase in women following menopause. Reactive oxygen species produced by normal aerobic cellular metabolism can lead to the release of free iron from ferritin. In the presence of superoxide radical and hydrogen peroxide, stored ferric iron (Fe(3+)) is reduced to ferrous iron (Fe(2+)), which catalyzes the formation of the hydroxyl radical (*OH). *OH in turn can promote lipid peroxidation, mutagenesis, DNA strand breaks, oncogene activation, and tumor suppressor inhibition, increasing the risk of breast cancer. In addition to its independent role as a proxidant, high levels of free iron may potentiate the effects of estradiol, ethanol, and ionizing radiation - three established risk factors for breast cancer. In order to identify the role of iron in breast carcinogenesis, improved biomarkers of body iron stores are needed, as are cohort studies which assess heme iron intake. Ultimately, it is important to determine whether iron levels in the breast and iron-induced pathology are higher in women who go on to develop breast cancer compared to women who do not.
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PMID:Does excess iron play a role in breast carcinogenesis? An unresolved hypothesis. 1782 49

Three of the most plausible biological theories of arsenic carcinogenesis are protein binding, oxidative stress and altered DNA methylation. This review presents the role of trivalent arsenicals binding to proteins in arsenic carcinogenesis. Using vacuum filtration based receptor dissociation binding techniques, the lifetimes of unidentate (<1s), bidentate (1-2min) and tridentate (1-2h) arsenite containing peptide binding complexes were estimated. According to our experimental data some of the protein targets to which arsenite may bind in vivo include tubulin, poly(ADP-ribose)polymerase (PARP-1), thioredoxin reductase, estrogen receptor-alpha, arsenic(+3)methyltransferase and Keap-1. Arsenite binding to tubulin can lead to several of the genetic effects observed after arsenic exposures (aneuploidy, polyploidy and mitotic arrests). Among many other possible arsenite binding sites are rat hemoglobin, the DNA repair enzyme xeroderma pigmentosum protein A (XPA), and other C2H2, C3H and C4 zinc finger proteins including members of the steroid receptor superfamily (e.g. glucocorticoid receptor). Macromolecules to which arsenite does not bind to include calf thymus DNA, mixed Type II-A histones and bovine H3/H4 histone. Although all six tested arsenicals released iron from ferritin, radioactive arsenite did not bind to the protein horse ferritin.
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PMID:The role of protein binding of trivalent arsenicals in arsenic carcinogenesis and toxicity. 1816 70

While exposure to fibers and particles has been proposed to be associated with several different lung malignancies including mesothelioma, the mechanism for the carcinogenesis is not fully understood. Along with mineralogical observation, we have analyzed forty-four major and trace elements in extracted asbestos bodies (fibers and proteins attached to them) with coexisting fiber-free ferruginous protein bodies from extirpative lungs of individuals with malignant mesothelioma. These observations together with patients' characteristics suggest that inhaled iron-rich asbestos fibers and dust particles, and excess iron deposited by continuous cigarette smoking would induce ferruginous protein body formation resulting in ferritin aggregates in lung tissue. Chemical analysis of ferruginous protein bodies extracted from lung tissues reveals anomalously high concentrations of radioactive radium, reaching millions of times higher concentration than that of seawater. Continuous and prolonged internal exposure to hotspot ionizing radiation from radium and its daughter nuclides could cause strong and frequent DNA damage in lung tissue, initiate different types of tumour cells, including malignant mesothelioma cells, and may cause cancers.
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PMID:Accumulation of radium in ferruginous protein bodies formed in lung tissue: association of resulting radiation hotspots with malignant mesothelioma and other malignancies. 1964 23


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