Arsenic activates NADPH oxidase through CDC42 and their involvement in actin filament remodeling and cell motility in endothelial cells.
Qian-Y; Flynn-DC; Castranova-V; Shi-X
Toxicologist 2004 Mar; 78(S-1):337
Although arsenic is a human carcinogen, the molecular mechanisms of its action remain to be understood. By stimulating mouse endothelial cell lines (SVEC4-10) with 10 uM arsenic, we found that arsenic induced activation of NADPH oxidase as determined by the nitroblue tetrazolium test. Using confocal microscopy, the generation of O2 and H2O2 was observed to be increased in SVEC4-10 cells after exposure to arsenic. We also found that arsenic activated Small Rho GTPase CDC42. Disruption of CDC42 with a dominant negative CDC42 abolished arsenic-induced activation of NADPH oxidase and subsequent generation of O2 and H2O2 suggesting that CDC42 may mediate the effects of arsenic on NADPH oxidase. Furthermore, it was found that arsenic stimulation induced actin filament remodeling increased cell motility in SVEC4-10 cells. These changes were abrogated by either disruption of CDC42 or inhibition of NADPH oxidase, indicating that the cell signaling changes induced by arsenic are relevant to these cellular functions. Taken together, the data imply that arsenic may promote motility-dependent metastasis of cancer cells through CDC42, NADPH oxidase and reactive oxygen species.
Arsenic-compounds; Carcinogens; Laboratory-animals; Animals; Animal-studies; Microscopy; Exposure-levels; Cellular-function
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland