Vittal Ragini, Selvanayagam Zachariah E, Sun Yi, Hong Jungil, Liu Fang, Chin Khew-Voon, Yang Chung S
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA.
Mol Cancer Ther. 2004 Sep;3(9):1091-9.
Many studies suggest green tea is a cancer chemopreventive agent. This effect has been attributed to its major constituent (-)-epigallocatechin-3-gallate (EGCG). EGCG is also observed to have cytotoxic anticancer effects, especially when used in combination with certain chemotherapeutic agents. The biochemical actions of EGCG in chemoprevention and anticancer effects have been studied; however, the mechanisms of action are not clearly understood. We show here by expression genomics the effects of EGCG (25 micromol/L) in the Ha-ras gene transformed human bronchial epithelial 21BES cells. We found induction of temporal changes in gene expression and the coalescence of specific genetic pathways by EGCG. In this experimental system, hydrogen peroxide (H2O2) was produced. By treating cells with EGCG in the presence or absence of catalase, we further distinguished gene expression changes that are mediated by H2O2 from those that are H2O2 independent. Many genes and cellular pathways, including genes of the transforming growth factor-beta signaling pathway, were H2O2 dependent because the effects were abolished by catalase. Gene expression changes that were not affected by catalase included those of the bone morphogenetic protein signaling pathway, peptidylprolyl isomerase (cyclophilin)-like 2, alkylated DNA repair enzyme alkB, polyhomeotic-like 2, and homeobox D1. We show further that EGCG and H2O2 differentially transactivated the bone morphogenetic protein and the transforming growth factor-beta response element promoter reporters, respectively, thus confirming results from DNA microarray analysis. The elucidation of gene expression changes between H2O2-dependent and H2O2-independent responses helps us better understand the cancer chemopreventive and anticancer actions of EGCG.
许多研究表明绿茶是一种癌症化学预防剂。这种作用归因于其主要成分（-）-表没食子儿茶素-3-没食子酸酯（EGCG）。EGCG还具有细胞毒性抗癌作用，尤其是与某些化疗药物联合使用时。人们已经研究了EGCG在化学预防和抗癌作用中的生化作用；然而，其作用机制尚不清楚。我们在此通过表达基因组学展示了EGCG（25微摩尔/升）对Ha-ras基因转化的人支气管上皮21BES细胞的影响。我们发现EGCG可诱导基因表达的时间变化以及特定基因途径的合并。在这个实验系统中，产生了过氧化氢（H2O2）。通过在有或没有过氧化氢酶的情况下用EGCG处理细胞，我们进一步区分了由H2O2介导的基因表达变化和与H2O2无关的变化。许多基因和细胞途径，包括转化生长因子-β信号通路的基因，都是H2O2依赖性的，因为过氧化氢酶可消除这些影响。不受过氧化氢酶影响的基因表达变化包括骨形态发生蛋白信号通路、肽基脯氨酰异构酶（亲环素）样2、烷基化DNA修复酶alkB、多同源样2和同源盒D1的基因表达变化。我们进一步表明，EGCG和H2O2分别差异性地反式激活骨形态发生蛋白和转化生长因子-β反应元件启动子报告基因，从而证实了DNA微阵列分析的结果。阐明H2O2依赖性和H2O2非依赖性反应之间的基因表达变化有助于我们更好地理解EGCG的癌症化学预防和抗癌作用。
