Nickel carcinogenesis: Epigenetics and hypoxia signaling

Costa, Max; Davidson, Thomas; Chen, Haobin; Ke, Qingdong; Zhang, Ping; Yan, Yan; Huang, Chuanshu; Kluz, Thomas

doi:10.1016/j.mrfmmm.2005.06.008

Cited by 184 publications

(126 citation statements)

References 22 publications

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“…So far, the data presented in this article support that the activation of IRP-1 by Ni(II), Co(II), V(V), and Mn(II) may be caused by cellular iron depletion, by competing with iron-dependent enzymes or DMT-1 iron transporter or both; Ni ions are able to prevent the degradation of HIF-1α protein by von Hippel Lindau (VHL) ubiquitin ligase by their inhibition of prolyl hydroxylases which target HIF-1α for degradation (Ivan et al, 2001;Jaakkola et al, 2001;Costa et al, 2005). Additionally, Ni ions induce HIF-1α protein by permitting its interaction with P300 by inhibiting the asparagines hydroxylase activity of FIH (Zhao et al, 2004).…”

Section: Discussionmentioning

confidence: 98%

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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Section: Discussionmentioning

confidence: 98%

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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“…Interestingly, a global increase in di-and tri-methylated H3-K9 was observed in human fetal type I lung cells and A549 human lung carcinoma cells subjected to hypoxia, concomitant with a global decrease in acetylated H3-K9 and H3-K14 [55,60]. This same combination of histone modifications, normally correlated with inactive gene expression, was found at the hypoxiarepressed surfactin protein A (Sp-A) gene, indicating that histone hypoacetylation and histone H3-K9-methylation are involved in hypoxia-induced transcription repression [60].…”

Section: Histone Methylation During Hypoxiamentioning

confidence: 98%

“…Lower cellular levels of acetyl-CoA during hypoxia [54] may, hypothetically, lead to a global decrease in histone acetylation levels [55]. Additionally, specifically regulated, enzymatic removal of acetyl-groups from histones and other proteins is provided by HDACs.…”

Section: Deacetylation and Hdacs During Hypoxiamentioning

confidence: 99%

Hypoxia-induced and stress-specific changes in chromatin structure and function

Johnson

Barton

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Cellular adaptation to stress relies on specific, regulated responses to evoke changes in gene expression. Stresses such as hypoxia, heat shock, oxidative stress and DNA-damage activate signaling cascades that ultimately lead to either induction or repression of stress-responsive genes. In this review, we concentrate on the mechanisms by which stress-induced signaling promotes alterations in chromatin structure, whether the read-out is activation or repression of transcription. Specific alterations in chromatin are highly regulated and dictated by the type of imposed stress. Our primary focus is on the types of chromatin alterations that occur under hypoxic conditions, which exist within a majority of tumors, and to compare these to changes in chromatin structure that occur in response to a wide variety of cellular stresses.

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“…As results, nickel compounds have been classified as established carcinogen to humans (Group 1) by the International Agency for Research on Cancer (IARC) in 1990 (10). Due to its weak mutagenesis, epigenetic changes have been implicated in nickel carcinogenesis (11)(12)(13). Disruption of cellular iron homeostasis by interfering with irondependent enzymes and generation of reactive oxygen species (ROS) also reportedly contribute to nickel carcinogenesis (14).…”

Section: Introductionmentioning

confidence: 99%

Activation of Akt/GSK3β and Akt/Bcl-2 signaling pathways in nickel-transformed BEAS-2B cells

Pan

Chang²,

Wang³

et al. 2011

Int J Oncol

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Abstract. The Akt signaling pathway has been implicated in a wide range of cellular functions involving cell survival and proliferation, angiogenesis, metabolism and cell migration. Accumulating evidence suggests that Akt perturbations play an important role in human malignancy. Here, we investigated Akt perturbation in nickel-transformed cells. Chronic treatment of human bronchial epithelial BEAS-2B cells with low doses of nickel chloride resulted in cell transformation demonstrated by anchorage-independent (AI) growth, increased cell growth and alterations of cell growth pattern. Western blot assays show that phosphorylation of Akt at Ser473, but not that of p38, JNK and ERK, was increased in nickel-transformed cells compared with controls. Inhibition of Akt or PI3K by pharmacological or biochemical interference suppressed nickel AI growth and cell growth of transformed cells. Activation of Akt led to inhibition of GSK3β by phosphorylation at Ser9 in nickel-transformed cells. In addition, two major anti-apoptotic proteins of the Bcl family, Bcl-2 and Bcl-XL, were increased in nickel-transformed cells. By employing the small interfering RNA technique (siRNA), our results showed that siRNA Akt attenuated the expression of Bcl-2 and Bcl-XL in nickel-transformed cells, indicating that induction of Bcl-2 and Bcl-XL was likely mediated through Akt. ROS generation was decreased in nickel-transformed cells compared with controls. Moreover, down-regulation of retinoblastoma protein (Rb) was observed in nickel-transformed cells. Taken together, these findings demonstrate that activation of Akt, followed by GSK3β inhibition and Bcl-2, Bcl-XL up-regulation and decrease of ROS generation, along with a synergistic effect of Rb down-regulation may cause apoptosis resistance, contributing to the overall mechanism of nickel carcinogenesis.

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Nickel carcinogenesis: Epigenetics and hypoxia signaling

Cited by 184 publications

References 22 publications

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

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

Hypoxia-induced and stress-specific changes in chromatin structure and function

Activation of Akt/GSK3β and Akt/Bcl-2 signaling pathways in nickel-transformed BEAS-2B cells

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