期刊
CHEMICO-BIOLOGICAL INTERACTIONS
卷 198, 期 1-3, 页码 38-48出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2012.05.004
关键词
Arsenite; Resveratrol; Epidermal growth factor; Extracellular signal-regulated kinases 1 and 2; Heme oxygenase-1; DNA polymerase beta
资金
- School of Human Life Sciences, University of Tasmania (Launceston, TAS)
- Electric Power Research Institute (EPRI) [WOEP-P4898/C2396]
Arsenic (As) is both a human carcinogen and an effective anticancer drug. These aspects of arsenic toxicity develop as a consequence of arsenic-induced oxidative stress and modifications to signal pathway activity which alter gene expression. Resveratrol (RVL) a food antioxidant found in grapes and other fruits, exhibits anti-carcinogenic properties by reducing oxidative stress and restoring signal pathway control. This study investigated the impact of RVL on arsenite [As(III)]-induced cell signalling in HaCaT keratinocytes by assaying phosphorylation status of epidermal growth factor receptor (EGFR) signalling intermediates and measuring changes in expression of Phase II and DNA repair biomarkers. As(III) exposure produced dose-dependent toxicity which was associated with increased activation of EGFR pathway intermediates, cSrc, Rac1 and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Arsenic-mediated ERK1/2 activation negatively regulated DNA polymerase beta expression and up regulated heme-oxygenase-1 at toxic concentrations. RVL treatment modulated As(III)-mediated ERK1/2 activation by shifting the balance of cSrc regulatory domain phosphorylation. These effects significantly altered the response of the EGFR pathway to growth factor-induced stimulation. Our research provides evidence that treatment with pharmacologically relevant doses of RVL influences cellular responses to As(III), largely due to RVL-mediated changes to Src and ERK1/2 activation. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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