Effects of soluble nickel on iron homeostasis: Possible role in nickel-mediated carcinogenesis.

摘要

Nickel compounds, other than metallic nickel, are well-established carcinogens and have been linked to carcinogenesis via in vitro, animal, and epidemiological studies. While the carcinogenic potential of insoluble nickel compounds has received much of the attention, soluble nickel compounds are now being realized as potent carcinogens, though their mechanisms of carcinogenesis remain unclear. Since soluble nickel compounds are not particularly effective in most mutagenesis assays, other mechanisms of carcinogenesis have been proposed. To better understand the possible carcinogenic mechanisms of soluble nickel, we investigated the effects of soluble nickel on iron homeostasis. Here, we provide evidence that nickel can alter cellular iron homeostasis and in turn, affect a variety of iron dependent processes in the cell. Exposure of A549 cells to soluble nickel significantly decreased total cellular iron levels, increased the binding of iron response protein-1 (IRP1), increased transferrin receptor mRNA, and blocked the induction of ferritin protein. This thesis also shows that the decreased cellular iron levels may be a result of competition at the divalent metal ion transporter-1 between nickel and iron. Additionally, soluble nickel was able to decrease the enzyme activity of iron-dependent enzymes, including aconitase, catalase, collagen prolyl-4-hydroxylase, and the hypoxia inducible factor-prolyl hydroxylases. The data indicate that the observed effect on the hypoxia inducible factor-prolyl hydroxylases may be a result of direct interference with this enzyme. The inhibition of the hypoxia inducible factor-prolyl hydroxylases by soluble nickel was shown to persistently induce hypoxia inducible factor-1alpha, a protein involved in carcinogenesis, angiogenesis, and metastasis, for up to 72 hours after nickel was removed from the media. The results presented here suggest that the effect of nickel on hypoxia inducible factor-prolyl hydroxylases and hypoxia inducible factor-1alpha may be an important factor in soluble nickel-mediated carcinogenesis. The observed effects of soluble nickel on a large variety of iron-dependent processes, including the activation of hypoxic responses are likely to be a key events in selection for a transformed phenotype. Understanding the mechanisms by which nickel can affect iron dependent processes in the cell may be important for the treatment of cancer and ischemic diseases.