Nickel carcinogenesis: Epigenetics and hypoxia signaling

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Abstract

Both water soluble and insoluble nickel compounds have been implicated in the etiology of human lung and nasal cancers. Water insoluble nickel compounds have been shown to enter cells by phagocytosis and are contained in cytoplasmic vacuoles, which are acidified thus accelerating the dissolution of soluble nickel from the particles. Using Newport Green, a dye that fluoresces when ionic nickel is bound, we have shown that following exposure (48–72 h) of human lung (A549) cells to NiS particles, most of the nickel is contained in the nucleus, while cells exposed to soluble NiCl2 exhibit most of the ions localized in the cytoplasm. This effect is consistent with previously published reports showing that short-term exposure of cells to crystalline nickel particles (1–3 days) is able to epigenetically silence target genes placed near heterochromatin, while similar short-term exposure to soluble nickel compounds are not able to induce silencing of genes placed near heterochromatin. However, a 3 week exposure of cells to soluble NiCl2 is also able to induce gene silencing. A similar effect was found in yeast cells where nickel was able to silence the URA-3 gene placed near (1.3 kb) a telomere silencing element, but not when the gene was placed farther away from the silencing element (2.0 kb). In addition to epigenetic effects, nickel compounds activate hypoxia signaling pathways. The mechanism of this effect involves the ability of either soluble or insoluble nickel compounds to block iron uptake leading to cellular iron depletion, directly affect iron containing enzymes, or both. This results in the inhibition of a variety of iron-dependent enzymes, such as aconitase and the HIF proline hydroxylases (PHD1-3). The inhibition of the HIF proline hydroxylases stabilizes the HIF protein and activates hypoxic signaling. Additional studies have shown that nickel and hypoxia decrease histone acetylation and increase the methylation of H3 lysine 9. These events are involved in gene silencing and hypoxia can also cause these effects in human cells. It is hypothesised that the state of hypoxia either by low oxygen tension or as a result of agents that signal hypoxia under normal oxygen tension (iron chelation, nickel and cobalt) results in low levels of acetyl CoA, which is a substrate for histone and other protein acetylation. This effect may in part be responsible for the gene silencing following nickel exposure and during hypoxia.

Introduction

Nickel compounds are well-established human carcinogens in occupationally exposed nickel refinery workers who have an excess incidence of lung and nasal cancer [1]. Both water soluble and insoluble nickel compounds have been implicated in the induction of these human cancers although animal studies reveal that the insoluble nickel compounds, such as Ni3S2 are more potent carcinogens than water soluble nickel compound [2], [3]. Work conducted in my laboratory has investigated the cellular mechanism by which water insoluble, as well as water soluble nickel compounds are carcinogenic [4], [5], [6]. Nickel compounds are not mutagenic and have been a useful tool to investigate alternate mechanism of carcinogenesis in addition to mutagenesis [7], [8]. This article will review the work conducted in my laboratory that describes the entry and cellular effects of both water soluble and insoluble nickel compounds on human and rodent cells in culture, as well as, discuss future directions for studying nickel carcinogenesis.

Section snippets

Uptake and intracellular distribution of nickel compounds

Fig. 1 shows the uptake and subcellular distribution of crystalline and amorphous nickel sulphide particles [9]. Carcinogenic crystalline particles, but not the non-carcinogenic amorphous nickel sulphide particles are phagocytized by cancer target cells and contained in cytoplasmic vacuoles that are acidified (pH 4.5) which accelerates the dissolution of nickel ions from the particles [10]. This process results in the accumulation of very high concentrations of soluble nickel inside the cell

Gene silencing by carcinogenic nickel compounds

The effect of nickel compounds on heterochromatin led to the discovery that nickel compounds could silence genes by inducing DNA methylation [20]. The gene on the X chromosome that was silenced by nickel compounds during its transformation of cells is believed by one investigator to be myeloid ELF-1-like factor (MEF/ELF-4) [21], [22], [23], although further work is required to substantiate this hypothesis. However, MEF is an interesting candidate gene, since loss of its expression will

The effect of nickel compounds in hypoxia signaling

In studying genes induced by nickel ions, we cloned a new gene that was induced by exposure to nickel compounds and named this gene Cap 43 [30]. This gene has also been named NDRG1 by another group since it had previously been cloned as an N-myc down regulated gene [31]. Further studies of NDRG1 showed that its induction was dependent upon the HIF-1 transcription factor, since neither the protein nor the RNA was increased by nickel in HIF-1α knock-out cells and hypoxia could also induce Cap

Other consequences of nickel exposure and hypoxia

When cells become hypoxic or are driven to this state by iron depletion via nickel exposure or iron chelation, the aerobic metabolism of cells via the Krebs cycle is likely suppressed, and ATP must be generated inefficiently by anaerobic glycolysis. A consequence of this is that the cellular level of acetyl CoA is likely to be lower since this is a substrate for the aerobic Krebs cycle generation of ATP. Interestingly, acetyl CoA is also the substrate for protein acetylation, which in the case

Acknowledgements

This work was supported by grant numbers ES00260, ES10344, and T32ES07324 from the NIH/NIEHS and CA16087 from the NIH/NCI.

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