Soluble nickel interferes with cellular iron homeostasis.
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.
Davidson
Todd
T
Nelson Institute of Environmental Medicine, School of Medicine, New York University, Tuxedo, New York 10987, USA.
Chen
Haobin
H
Garrick
Michael D
MD
D'Angelo
Gisela
G
Costa
Max
M
D001667:Binding, Competitive; D002273:Carcinogens / Q000633:toxicity*; D027682:Cation Transport Proteins / Q000378:metabolism; D002460:Cell Line; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D009532:Nickel / Q000633:toxicity*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D012995:Solubility; D013997:Time Factors; D014168:Transferrin / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
D002273:Carcinogens; D027682:Cation Transport Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron; D009532:Nickel; D011393:Procollagen-Proline Dioxygenase; D014168:Transferrin; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099236:Solute Carrier Family 11, Member 2; C497442:HIF1A protein, human; C497446:VHL protein, human