Hydrogen peroxide mediates activation of nuclear factor of activated T cells (NFAT) by nickel subsulfide.
Nickel compounds induce cell transformation in cell culture models and tumor formation in experimental animals. However, the molecular mechanisms by which nickel compounds induce tumors are not yet well understood. The present study found that exposure of cells to either Ni(3)S(2) or NiCl(2) could result in specific transactivation of nuclear factor of activated T cells (NFAT), although it did not show any activation of p53 or AP-1. Furthermore, nickel compounds were also able to cause generation of reactive oxygen species (ROS). The scavenging of nickel-induced H(2)O(2) with N-acety-L-cyteine (a general antioxidant) or catalase, or the chelation of nickel with deferoxamine, resulted in inhibition of NFAT activation. In contrast, pretreatment of cells with sodium formate (an .OH radical scavenger) or superoxide dismutase (an O(-.)(2) radical scavenger) did not show any inhibitory effects. These results demonstrate that nickel compounds are able to induce NFAT activation, and that the mechanism of NFAT activation seems to be mediated by the generation of H(2)O(2) by these metal compounds. This study should help us understand the signal transduction pathways involved in carcinogenic effects of these nickel compounds.
Huang
C
C
Nelson Institute of Environmental Medicine and Kaplan Comprehensive Cancer Center, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA. chuanshu@env.med.nyu.edu
Li
J
J
Costa
M
M
Zhang
Z
Z
Leonard
S S
SS
Castranova
V
V
Vallyathan
V
V
Ju
G
G
Shi
X
X
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D003676:Deferoxamine / Q000494:pharmacology; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors; D009532:Nickel / Q000633:toxicity*; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection
D002273:Carcinogens; D002614:Chelating Agents; D004268:DNA-Binding Proteins; D016166:Free Radical Scavengers; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D019284:Thapsigargin; C022838:nickel chloride; D009532:Nickel; D016572:Cyclosporine; D006861:Hydrogen Peroxide; D019703:Calcineurin; D003676:Deferoxamine; D002118:Calcium; D000111:Acetylcysteine; C017557:nickel subsulfide