Hydrogen peroxide mediates activation of nuclear factor of activated T cells (NFAT) by nickel subsulfide.
Huang-C; Li-J; Costa-M; Zhang-Z; Leonard-SS; Castranova-V; Vallyathan-V; Ju-G; Shi-X
Cancer Res 2001 Nov; 61(22):8051-8057
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.
Peroxides; Nickel-compounds; Sulfides; Cell-transformation; Cell-cultures; Animal-studies; Tumors
Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987
Cancer Research Methods; Cancer; Disease and Injury