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Arch Toxicol. 2012 Jun;86(6):935-45. doi: 10.1007/s00204-012-0856-9. Epub 2012 Apr 25.

NADPH oxidase-produced superoxide mediates EGFR transactivation by c-Src in arsenic trioxide-stimulated human keratinocytes.

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1
Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.

Abstract

Arsenic is a well-known poison and carcinogen in humans. However, it also has been used to effectively treat some human cancers and non-carcinogenic ailments. Previously, we demonstrated in keratinocytes that arsenic trioxide (ATO)-induced p21(WAF1/CIP1) (p21) expression leading to cellular cytotoxicity through the c-Src/EGFR/ERK pathway and generation of reactive oxygen species (ROS). In this study, we found that EGFR-Y845 and EGFR-Y1173 could be phosphorylated by ATO. Using confocal microscopy and flow cytometry, we found that pretreatment with apocynin, DPI, and tiron could remove ATO-induced ROS production. Furthermore, to increase NADPH oxidase activity, ATO could induce cytosolic p67(phox) expression and translocation to membrane. In addition, knockdown of p67(phox) could abolish ATO-induced ROS production. Therefore, we suggest that NADPH oxidase-produced superoxide was a major source of ATO-induced ROS production. Conversely, ATO-induced NADPH oxidase activation and superoxide generation could be inhibited by the c-Src inhibitor PP1, but not by the EGFR inhibitor PD153035. In addition, overexpression of c-Src as well as treatment with ATO could stimulate EGFR-Y845/ERK phosphorylation, p21 expression, and cellular arrest/apoptosis, which could be attenuated by pretreatment with apocynin or knockdown of p67(phox). Collectively, we suggest that NADPH oxidase was involved in the ATO-induced arrest/apoptosis of keratinocytes, which was regulated by c-Src activation.

PMID:
22532027
DOI:
10.1007/s00204-012-0856-9
[Indexed for MEDLINE]
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