Nickel decreases cellular iron level and converts cytosolic aconitase to iron-regulatory protein 1 in A549 cells

Chen, Haobin; Davidson, Thomas; Singleton, Steven T.; Garrick, Michael D.; Costa, Max

doi:10.1016/j.taap.2004.11.011

Cited by 72 publications

(61 citation statements)

References 54 publications

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“…It has been suggested that interference with intracellular iron homeostasis, oxidation/ depletion of ascorbic acid that is also an essential cofactor for most of the dioxygenases in this family, and direct binding to the enzyme may collectively contribute to the ability of nickel ions to inhibit iron-and 2-oxoglutarate-dependent dioxygenases (39,52,53). Because interference with intracellular iron homeostasis and oxidation/depletion of ascorbic acid are readily correctable after removal of nickel ions, these dioxygenases would be easily reactivated.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that HIF prolyl hydroxylase PHD2 was 20 times more sensitive to nickel inhibition when compared with aconitase that binds iron in the form of [4Fe-4S] cluster (38,39). An interesting question is whether these newly identified histone demethylases and the other members in this Fe(II)-and 2-oxoglutarate-dependent dioxygenase family have similar sensitivity to nickel inhibition as PHD2.…”

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confidence: 99%

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Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers

Chen

Giri

Zhang

et al. 2010

Journal of Biological Chemistry

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131

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Iron-and 2-oxoglutarate-dependent dioxygenases are a diverse family of non-heme iron enzymes that catalyze various important oxidations in cells. A key structural motif of these dioxygenases is a facial triad of 2-histidines-1-carboxylate that coordinates the Fe(II) at the catalytic site. Using histone demethylase JMJD1A and DNA repair enzyme ABH2 as examples, we show that this family of dioxygenases is highly sensitive to inhibition by carcinogenic nickel ions. We find that, with iron, the 50% inhibitory concentrations of nickel (IC 50 Nickel compounds are human respiratory carcinogens (1), causing a very high incidence of lung and nasal cancers in nickel refinery workers (2). Over 20 years ago, our group reported that cells phagocytosed particulate nickel compounds, and the dissolution of these particles inside of the cells generated high concentrations of free nickel ions in the cytoplasm and nucleus (3). Using a dye that fluoresces when intracellular nickel ion binds to it, we showed that both soluble and insoluble nickel compounds were able to elevate the levels of nickel ions in the cytoplasmic and nuclear compartments (4). A strong correlation was found between the uptake of particulate nickel compounds by cells and subsequent cell transformation (5), suggesting that intracellular nickel ion concentration is a major determinant of toxicity and carcinogenicity of nickel compounds. Identifying the intracellular targets of nickel ions is therefore crucial to understand the underlying mechanism for the carcinogenic effects of nickel compounds.Silencing of tumor suppressor gene(s) by epigenetic mechanisms represents one of the potential mechanisms of nickel carcinogenesis. Epigenetic events, which include DNA methylation and histone modifications, are ubiquitously involved in the regulation of gene expression. By using a transgenic cell model with the target gene placed near heterochromatin, we were the first to demonstrate that nickel exposure caused a very high frequency of transgene silencing by increasing DNA methylation and repressive histone marks at the promoter of the silenced transgene (6 -8). In animal experiments, injection of particulate nickel compounds (nickel sulfide or nickel subsulfide) into mice induced formation of malignant fibrous histiocytomas and sarcomas, with the p16 and Fhit genes often found to be epigenetically silenced in these cancers (9,10). Additional studies have demonstrated that nickel exposure caused truncation of histone H2B and H2A as well as global alterations of a variety of histone modifications, such as histone acetylation, methylation, phosphorylation, and ubiquitination (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). However, the underlying mechanisms responsible for these nickel-induced epigenetic alterations are poorly understood. In our recent study, we reported that nickel increases the global levels of mono-and di-methylated histone H3 lysine 9 (H3K9me1 and H3K9me2) not by affecting histone methyltransferases but rather by inhibiting a group of unidentified iron-and...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers

Chen

Giri

Zhang

et al. 2010

Journal of Biological Chemistry

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131

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“…All metals are potentially toxic at high concentration, even though some are also essential. Metal ions were selected for this study because some of them, including nickel, manganese, and aluminum, have been shown to alter iron homeostasis following exposure in a number of different cell types (Zheng et al, 1999;Ward et al, 2001;Chen et al, 2005), which may contribute to the mechanism by which these metals exert their adverse effects on living organisms.…”

Section: Introductionmentioning

confidence: 99%

“…One is that the metal ion competes with iron for iron transport proteins such as transferrin or DMT-1 (Ward et al, 2001;Chen et al, 2005); while the other is that the metal ion interferes with iron homeostasis at the level of IRPs by competing with iron for the fourth, labile iron site in [4Fe-4S] cluster and thereby activates IRP binding (Zheng and Zhao, 2001). Since our previous study showed that Ni ions decreased intracellular Fe levels in A549 human lung cells by competing with iron for DMT-1 , and recently DMT-1 was identified as the major iron transporter in lung epithelia (Wang et al, 2002), it suggests that nickel altered iron homeostasis probably by competing with iron for DMT-1 in A549 cells.…”

Section: Introductionmentioning

confidence: 99%

Effects of 12 metal ions on iron regulatory protein 1 (IRP-1) and hypoxia-inducible factor-1 alpha (HIF-1α) and HIF-regulated genes

Chen

Huang

et al. 2006

Toxicology and Applied Pharmacology

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Several metal ions that are carcinogenic affect cellular iron homeostasis by competing with iron transporters or iron-regulated enzymes. Some metal ions can mimic a hypoxia response in cells under normal oxygen tension, and induce expression of HIF-1α-regulated genes. This study investigated whether 12 metal ions altered iron homeostasis in human lung carcinoma A549 cells as measured by an activation of IRP-1 and ferritin level. We also studied hypoxia signaling by measuring HIF-1α protein levels, hypoxia response element (HRE)-driven luciferase reporter activity, and Cap43 protein level (an HIF-1α responsive gene). Our results show the following: (i) Ni(II), Co(II), V(V), Mn(II), and to a lesser extent As(III) and Cu(II) activated the binding of IRP-1 to IRE after 24 h, while the other metal ions had no effect; (ii) 10 of 12 metal ions induced HIF-1α protein but to strikingly different degrees. Two of these metal ions, Al(III) and Cd(II), did not induce HIF-1α protein; however, as indicated below, only Ni(II), Co (II), and to lesser extent Mn(II) and V(V) activated HIF-1α-dependent transcription. The combined effects of both [Ni(II) + As(III)] and [Ni (II) + Cr(VI)] on HIF-1α protein were synergistic; (iii) Addition of Fe(II) with Ni(II), Co(II), and Cr (VI) attenuated the induction of HIF-1α after 4 h treatment; (iv) Ni(II), Co(II), and Mn(II) significantly decrease ferritin level after 24 h exposure; (v) Ni(II), Co(II), V (V), and Mn(II) activated HRE reporter gene after 20 h treatment; (vi) Ni(II), Co(II), V(V), and Mn(II) increased the HIF-1-dependent Cap43 protein level after 24 h treatment. In conclusion, only Ni (II), Co (II), and to a lesser extent Mn(II) and V(V) significantly stabilized HIF-1α protein, activated IRP, decreased the levels of ferritin, induced the transcription of HIF-dependent reporter, and increased the expression of Cap43 protein levels (HIF-dependent gene). The mechanism for the significant stabilization and elevation of HIF-1α protein which drives these other parameters was previously shown by us and others to involve a loss of cellular Fe as well as inhibition of HIF-1α-dependent prolyl hydroxylases which target the binding of VHL ubiquitin ligase and degrade HIF-1α. Even though there were small effects of some of the other metals on IRP and HIF-1α, downstream effects of HIF-1α activation and therefore robust hypoxia signaling were only observed with Ni(II), Co(II), and to much lesser extents with Mn(II) and V(V) in human A549 lung cells. It is of interest that the metal ions that were most effective in activating hypoxia signaling were the ones that were poor inducers of metallothionein protein and also decreased Ferritin levels, since both of these proteins can bind metal ions and protect the cell against toxicity in human lung cells. It is important to study effects of these metals in human lung cells since this represents a major route of human environmental and occupational exposure to these metal ions.

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“…Ni-Ti wires may thus induce nickel hypersensitivity, and nickel-sensitive patients are recommended to avoid this wire. 12,13 Moreover, recently numerous animal studies concerning the carcinogenicity of nickel have been reported, [14][15][16] though some early studies suggested that nickel did not give rise to cancer in animals. 17 Titanium-molybdenum alloy has been used for a nickel-free orthodontic wire.…”

Section: Introductionmentioning

confidence: 99%

Orthodontic Buccal Tooth Movement by Nickel-Free Titanium-Based Shape Memory and Superelastic Alloy Wire

Suzuki

Kanetaka

Shimizu

et al. 2006

The Angle Orthodontist

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Objective: To examine the mechanical properties and the usefulness of titanium-niobium-aluminum (Ti-Nb-Al) wire in orthodontic tooth movement as compared with nickel-titanium (Ni-Ti) wire. Materials and Methods: The load deflection of expansion springs was gauged with an original jig. The gradient of the superelastic region was measured during the unloading process. Expansion springs comprising the two types of alloy wires were applied to upper first molars of rats. The distance between the first molars was measured with micrometer calipers. Results: The force magnitude of the Ti-Nb-Al expansion spring was lower than that of the Ni-Ti expansion spring over the entire deflection range. The initial force magnitude and the gradient in the superelastic region of the Ti-Nb-Al expansion springs were half those of the Ni-Ti expansion springs. Thus, Ti-Nb-Al expansion springs generated lighter and more continuous force. Tooth movement in the Ni-Ti group proceeded in a stepwise fashion. On the other hand, tooth movement in the Ti-Nb-Al group showed relatively smooth and continuous progression. At 17 days after insertion of expansion springs, there were no significant differences between the Ti-Nb-Al and NiTi groups in the amount of tooth movement. Conclusions:These results indicate that Ti-Nb-Al wire has excellent mechanical properties for smooth, continuous tooth movement and suggest that Ti-Nb-Al wire may be used as a practical nickel-free shape memory and superelastic alloy wire for orthodontic treatment as a substitute for Ni-Ti wire.

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Nickel decreases cellular iron level and converts cytosolic aconitase to iron-regulatory protein 1 in A549 cells

Cited by 72 publications

References 54 publications

Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers

Nickel Ions Inhibit Histone Demethylase JMJD1A and DNA Repair Enzyme ABH2 by Replacing the Ferrous Iron in the Catalytic Centers

Effects of 12 metal ions on iron regulatory protein 1 (IRP-1) and hypoxia-inducible factor-1 alpha (HIF-1α) and HIF-regulated genes

Orthodontic Buccal Tooth Movement by Nickel-Free Titanium-Based Shape Memory and Superelastic Alloy Wire

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