Soluble nickel interferes with cellular iron homeostasis

Mol Cell Biochem. 2005 Nov;279(1-2):157-62. doi: 10.1007/s11010-005-8288-y.


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-1alpha (HIF-1alpha). Nickel was able to decrease the binding of the Von Hippel-Lindau (VHL) protein to HIF-1alpha, 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-1alpha pathway may lead to new molecular targets in fighting cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding, Competitive
  • Carcinogens / toxicity*
  • Cation Transport Proteins / metabolism
  • Cell Line
  • Homeostasis / drug effects*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Iron / metabolism*
  • Nickel / toxicity*
  • Procollagen-Proline Dioxygenase / antagonists & inhibitors
  • Procollagen-Proline Dioxygenase / metabolism
  • Solubility
  • Time Factors
  • Transferrin / metabolism
  • Von Hippel-Lindau Tumor Suppressor Protein / antagonists & inhibitors
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism


  • Carcinogens
  • Cation Transport Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Transferrin
  • solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
  • Nickel
  • Iron
  • Procollagen-Proline Dioxygenase
  • Von Hippel-Lindau Tumor Suppressor Protein
  • VHL protein, human