Abstract
Although arsenic is a human carcinogen, the molecular mechanisms of its action remain to be understood. The present study reports that exposure to arsenic induced actin filament reorganization, resulting in lamellipodia and filopodia structures through the activation of Cdc42 in SVEC4-10 endothelial cells. It was also found that arsenic induced the formation of the superoxide anion (O2*) in SVEC4-10 cells. Immunoprecipitation and Western blotting analysis demonstrated that arsenic stimulation induced serine phosphorylation of p47phox, a key component of NADPH oxidase, indicating that arsenic induces O2* formation through NADPH oxidase activation. Inhibition of arsenic-induced actin filament reorganization by either overexpression of a dominant negative Cdc42 or pretreatment of an actin filament stabilizing regent, jasplakinolide, abrogated arsenic-induced NADPH oxidase activation, showing that the activation of NADPH oxidase was regulated by Cdc42-mediated actin filament reorganization. This study also showed that overexpression of a dominant negative Rac1 was sufficient to abolish arsenic-induced O2*- production, implying that Rac1 activities are required for Cdc42-mediated NADPH oxidase activation in response to arsenic stimulation. Furthermore, arsenic stimulation induced cell migration, which can be inhibited by the inactivation of either Cdc42 or NADPH oxidase. Taken together, the results indicate that arsenic is able to activate NADPH oxidase through Cdc42-mediated actin filament reorganization, leading to the induction of an increase in cell migration in SVEC4-10 endothelial cells.
Highlights
Arsenic has long been considered a toxic and carcinogenic metal
We demonstrated that arsenic stimulation induced actin filament reorganization to form lamellipodia and filopodia structures through the activation of
Our results demonstrated that arsenic stimulation was sufficient to induce actin filament reorganization to form lamellipodia and filopodia structures at the leading edge of the cells and rosette-like structures in the cell body in SVEC4-10 endothelial cells, indicating that actin cytoskeleton architecture is a molecular target of arsenic-induced stress injury in endothelial cells
Summary
3875–3884, 2005 Printed in U.S.A. Cdc Regulates Arsenic-induced NADPH Oxidase Activation and Cell Migration through Actin Filament Reorganization*. The present study reports that exposure to arsenic induced actin filament reorganization, resulting in lamellipodia and filopodia structures through the activation of Cdc in SVEC4-10 endothelial cells. The results indicate that arsenic is able to activate NADPH oxidase through Cdc42-mediated actin filament reorganization, leading to the induction of an increase in cell migration in SVEC4-10 endothelial cells. The present study attempts to understand the mechanisms of arsenic-induced NADPH oxidase activation and cell migration with an emphasis on the involvement of Cdc and actin filament reorganization. The results of this study provided the first evidence showing that Cdc42-induced actin filament reorganization mediates the activation of NADPH oxidase
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