US EPA

1248948 

Journal Article 

Modulation of arsenic-induced epidermal growth factor receptor pathway signalling by resveratrol 

Herbert, KJ; Snow, ET 

2012 

Yes 

Chemico-Biological Interactions
ISSN: 0009-2797
EISSN: 1872-7786 

198 

1-3 

38-48 

English 

22634503 

10.1016/j.cbi.2012.05.004 

WOS:000306778300005 

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. 

Arsenite; Resveratrol; Epidermal growth factor; Extracellular signal-regulated kinases 1 and 2; Heme oxygenase-1; DNA polymerase beta