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Soluble nickel interferes with cellular iron homeostasis
Todd Davidson1, Haobin Chen, Michael D Garrick
1Nelson Institute of Environmental Medicine, School of Medicine, New York University, Tuxedo, New York 10987, USA.
Molecular and Cellular Biochemistry
|November 12, 2005
Summary
Soluble nickel compounds, a potential carcinogen, disrupt cellular iron by entering cells via DMT1 and interfering with iron-dependent processes. This mechanism may contribute to nickel-induced cancer development.
Area of Science:
- Environmental toxicology
- Molecular carcinogenesis
- Cellular metal homeostasis
Background:
- Soluble nickel compounds are recognized as probable human carcinogens.
- The precise mechanisms underlying nickel-induced carcinogenesis remain incompletely understood.
- Existing hypotheses suggest nickel's role in disrupting cellular processes.
Purpose of the Study:
- To investigate nickel's cellular uptake mechanism.
- To determine nickel's impact on cellular iron homeostasis.
- To elucidate nickel's interference with iron-dependent enzymatic activities.
Main Methods:
- Utilized the divalent metal ion transporter 1 (DMT1) pathway for nickel entry.
- Assessed nickel's effects on extracellular and intracellular iron availability.
- Examined nickel's competition for iron-binding sites on enzymes, specifically prolyl hydroxylases.
Main Results:
- Confirmed nickel entry into cells via DMT1.
- Demonstrated nickel's disruption of cellular iron homeostasis.
- Showed nickel decreases prolyl hydroxylase activity by reducing Von Hippel-Lindau (VHL) protein binding to hypoxia-inducible factor-1alpha (HIF-1alpha).
Conclusions:
- Nickel's interference with iron homeostasis and iron-dependent enzymes is a key step in nickel carcinogenesis.
- Understanding nickel-mediated HIF-1alpha pathway activation may reveal novel therapeutic targets for cancer treatment.