Journal article
NADPH oxidase activation is required in reactive oxygen species generation and cell transformation induced by hexavalent chromium
Toxicological sciences, Vol.123(2), pp.399-410
10/2011
DOI: 10.1093/toxsci/kfr180
PMCID: PMC3179675
PMID: 21742780
Abstract
Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Although overproduction of reactive oxygen species (ROS) has been suggested to play a major role in its carcinogenicity, the mechanisms of Cr(VI)-induced ROS production remain unclear. In this study, we investigated the role of NADPH oxidase (NOX), one of the major sources of cellular ROS, in Cr(VI)-induced oxidative stress and carcinogenesis. We found that short-term exposure to Cr(VI) (2μM) resulted in a rapid increase in ROS generation in Beas-2B cells, and concomitantly increased NOX activity and expression of NOX members (NOX1-3 and NOX5) and subunits (p22(phox), p47(phox), p40(phox), and p67(phox)). Cr(VI) also induced phosphorylation of p47(phox) and membrane translocation of p47(phox) and p67(phox), further confirming NOX activation. Knockdown of p47(phox) with a short hairpin RNA attenuated the ROS production induced by Cr(VI). Chronic exposure (up to 3 months) to low doses of Cr(VI) (0.125, 0.25, and 0.5μM) also promoted ROS generation and the expression of NOX subunits, such as p47(phox) and p67(phox), but inhibited the expression of main antioxidant enzymes, such as superoxidase dismutase (SOD) and glutathione peroxidase (GPx). Chronic Cr(VI) exposure resulted in transformation of Beas-2B cells, increasing cell proliferation, anchorage independent growth in soft agar, and forming aggressive tumors in nude mice. Stable knockdown of p47(phox) or overexpression of SOD1, SOD2, or catalase (CAT) eliminated Cr(VI)-induced malignant transformation. Our results suggest that NOX plays an important role in Cr(VI)-induced ROS generation and carcinogenesis.
Details
- Title: Subtitle
- NADPH oxidase activation is required in reactive oxygen species generation and cell transformation induced by hexavalent chromium
- Creators
- Xin Wang - University of KentuckyYoung-Ok Son - University of KentuckyQingshan Chang - University of KentuckyLijuan Sun - University of KentuckyJ Andrew Hitron - University of KentuckyAmit Budhraja - University of KentuckyZhuo Zhang - University of KentuckyZunji Ke - Chinese Academy of SciencesFei Chen - University of KentuckyJia Luo - University of KentuckyXianglin Shi - University of Kentucky
- Resource Type
- Journal article
- Publication Details
- Toxicological sciences, Vol.123(2), pp.399-410
- DOI
- 10.1093/toxsci/kfr180
- PMID
- 21742780
- PMCID
- PMC3179675
- ISSN
- 1096-6080
- eISSN
- 1096-0929
- Grant note
- 1R01ES015518 / NIEHS NIH HHS 1R01CA119028 / NCI NIH HHS 1R01CA116697 / NCI NIH HHS R01 ES015375 / NIEHS NIH HHS T32 ES007266 / NIEHS NIH HHS R01 ES015518 / NIEHS NIH HHS R01 CA116697 / NCI NIH HHS R01 CA119028 / NCI NIH HHS
- Language
- English
- Date published
- 10/2011
- Academic Unit
- Pathology
- Record Identifier
- 9984201114802771
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