Cdc42 regulates arsenic-induced NADPH oxidase activation and cell migration through actin filament reorganization.
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.
Qian
Yong
Y
Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA. YAQ2@CDC.GOV
Liu
Ke Jian
KJ
Chen
Yan
Y
Flynn
Daniel C
DC
Castranova
Vince
V
Shi
Xianglin
X
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D001151:Arsenic / Q000494:pharmacology*; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D011554:Pseudopodia / Q000187:drug effects / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D019255:NADPH Oxidases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D001151:Arsenic