Journal
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Volume 41, Issue 4, Pages 945-956Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2008.09.028
Keywords
Resveratrol; H2O2; Caspase; NHE-1; AP2
Categories
Funding
- Ministry of Education, Singapore
- BMRC
- NMRC, Singapore
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Na+/H+ exchanger-1 (NHE-1) overexpression is associated with carcinogenesis and is an attractive target for intervention. We report that the chemopreventive agent resveratrol (RSV) downregulates NHE-1 in a caspase-dependent manner without inducing cell death. Resveratrol triggered early activation of caspase 3 and late activation of caspase 6, which were not inter-de pendent. Whereas, caspase 3 activation appeared to be a direct effect of resveratrol, caspase 6 activation was mediated via intracellular hydrogen peroxide production and iron. Moreover, down regulation of NHE-1 expression was a function of resveratrol-induced repression of NHE-1 gene promoter activity. RNAi-mediated silencing of caspase 3 or 6 blocked the effect of resveratrol on NHE-1 expression, however the effect on NHE-1 promoter was observed at different phases of promoter repression with caspase 3 controlling the early phase (4-12 h) and caspase 6 regulating the late phase (12-24h). Scavenging hydrogen peroxide or iron only reversed the late phase of resveratrol-induced NHE-1 promoter repression. Finally, an AP2 binding region within NHE-1 gene promoter was identified as the target of resveratrol. Collectively, these data could explain the anti-cancer activity of resveratrol in the light of the association of increased NHE-1 expression with carcinogenesis. (C) 2008 Elsevier Ltd. All rights reserved.
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