Resveratrol regulates the expression of NHE-1 by repressing its promoter activity: Critical involvement of intracellular H2O2 and caspases 3 and 6 in the absence of cell death
Resveratrol regulates the expression of NHE-1 by repressing its promoter activity: Critical involvement of intracellular H2O2 and caspases 3 and 6 in the absence of cell death
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DOI：
10.1016/j.biocel.2008.09.028
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发表时间：
2009-04-01
影响因子：
4
通讯作者：
Clement, Marie-Veronique
中科院分区：
文献类型：
--
作者：
Jhumka, Ziyad;Pervaiz, Shazib;Clement, Marie-Veronique
Na+/H+交换器-1（NHE-1）过表达与肿瘤发生有关，是一个有吸引力的干预靶点。我们报告说，化学预防剂白藜芦醇（RSV）下调NHE-1在半胱天冬酶依赖的方式，而不诱导细胞死亡。白藜芦醇可激活caspase 3的早期激活和caspase 6的晚期激活，二者之间无相互依赖关系。而caspase 3的激活似乎是白藜芦醇的直接作用，caspase 6的激活通过细胞内过氧化氢的产生和铁介导。此外，NHE-1表达的下调是白藜芦醇诱导的NHE-1基因启动子活性抑制的功能。RNA干扰抑制caspase 3或6可阻断白藜芦醇对NHE-1基因表达的影响，但对NHE-1启动子的影响存在于启动子抑制的不同阶段，caspase 3控制早期（4-12 h），caspase 6控制晚期（12- 24 h）。清除过氧化氢或铁只逆转白藜芦醇诱导的NHE-1启动子抑制的晚期。最后，NHE-1基因启动子内的AP 2结合区被确定为白藜芦醇的靶点。总的来说，这些数据可以解释白藜芦醇的抗癌活性的光的增加NHE-1表达与致癌作用。(C)2008爱思唯尔有限公司保留所有权利。
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.