Jhumka Ziyad, Pervaiz Shazib, Clément Marie-Veronique
Department of Biochemistry, Yong Loo Lin School of Medicine, Singapore.
Int J Biochem Cell Biol. 2009 Apr;41(4):945-56. doi: 10.1016/j.biocel.2008.09.028. Epub 2008 Oct 4.
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-dependent. 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, downregulation 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 (12-24 h). 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.
钠/氢交换体1（NHE-1）的过表达与肿瘤发生相关，是一个有吸引力的干预靶点。我们报道化学预防剂白藜芦醇（RSV）以半胱天冬酶依赖的方式下调NHE-1，且不诱导细胞死亡。白藜芦醇触发了半胱天冬酶3的早期激活和半胱天冬酶6的晚期激活，二者并非相互依赖。虽然，半胱天冬酶3的激活似乎是白藜芦醇的直接作用，但半胱天冬酶6的激活是通过细胞内过氧化氢生成和铁介导的。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结果。RNA干扰介导的半胱天冬酶3或6的沉默阻断了白藜芦醇对NHE-1表达的影响，然而在启动子抑制的不同阶段观察到对NHE-1启动子的影响，半胱天冬酶3控制早期阶段（4 - 12小时），半胱天冬酶6调节晚期阶段（12 - 24小时）。清除过氧化氢或铁仅逆转了白藜芦醇诱导的NHE-1启动子抑制的晚期阶段。最后，NHE-1基因启动子内的一个AP2结合区域被确定为白藜芦醇的作用靶点。总体而言，鉴于NHE-1表达增加与肿瘤发生的关联，这些数据可以解释白藜芦醇的抗癌活性。
