Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
Nickel carcinogenesis: Epigenetics and hypoxia signaling
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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