Soluble nickel interferes with cellular iron homeostasis

Todd Davidson, Haobin Chen, Michael D. Garrick, Gisela D'Angelo, Max Costa

Research output: Contribution to journalArticlepeer-review

68 Scopus citations

Abstract

Soluble nickel compounds are likely human carcinogens. The mechanism by which soluble nickel may contribute to carcinogenesis is unclear, though several hypotheses have been proposed. Here we verify the ability of nickel to enter the cell via the divalent metal ion transporter 1 (DMT1) and disturb cellular iron homeostasis. Nickel may interfere with iron at both an extracellular level, by preventing iron from being transported into the cell, and at an intracellular level, by competing for iron sites on enzymes like the prolyl hydroxylases that modify hypoxia inducible factor-1α (HIF-1α). Nickel was able to decrease the binding of the Von Hippel-Lindau (VHL) protein to HIF-1α, indicating a decrease in prolyl hydroxylase activity. The ability of nickel to affect various iron dependent processes may be an important step in nickel dependent carcinogenesis. In addition, understanding the mechanisms by which nickel activates the HIF-1α pathway may lead to new molecular targets in fighting cancer.

Original languageEnglish
Pages (from-to)157-162
Number of pages6
JournalMolecular and Cellular Biochemistry
Volume279
Issue number1-2
DOIs
StatePublished - Nov 2005

Keywords

  • Divalent metal ion transporter-1
  • HIF-1α
  • Iron
  • Nickel
  • Prolyl hydroxylase
  • Von Hippel-Lindau

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