Department of Genetics and Molecular Biology, Center for Research and Advance Studies-National Polytechnic Institute, México DF, Mexico.
Eur J Cancer Prev. 2013 Jan;22(1):11-20. doi: 10.1097/CEJ.0b013e328353edcb.
To gain insights into the antitumor mechanisms of resveratrol (RES), we carried out a DNA microarray analysis in the breast cancer cell line MCF-7 to study the global gene expression profile induced by RES treatment. The mRNA expression level of 19 734 well-characterized human genes from MCF-7 cells was determined using Affymetrix microarrays under two different RES treatments: 150 μmol/l (IC(50)) and 250 μmol/l during 48 h. A total of 1211 genes were found to have altered mRNA expression levels of two-fold or more in the 150 μmol/l RES-treated group (518 upregulated and 693 downregulated genes). However, 2412 genes were found to have altered expression levels of two-fold or more in the 250 μmol/l RES-treated group (651 genes upregulated and 1761 downregulated). Under both conditions of RES treatment, several genes of mismatch repair, DNA replication, homologous recombination (HR), and cell cycle were strongly inhibited. Consistently, we found decreased protein levels of the MRN complex (MRE11-NBS1-RAD50), an important complex of the HR DNA repair pathway. The ability to inhibit the expression of DNA repair genes by RES could help to overcome drug resistance commonly shown by transformed cells and to provide a solid basis for carrying out clinical trials with RES, alone or in combination with other agents, to enhance treatment efficacy, reduce toxicity, and overcome chemoresistance. Remarkably, after RES treatment, we found a decrease in NBS1 and MRE11 protein levels, two major proteins involved in HR, which suggests that RES could be used to sensitize cancer cells to cell death in combination with anticancer drugs.
为了深入了解白藜芦醇（RES）的抗肿瘤机制，我们在乳腺癌细胞系 MCF-7 中进行了 DNA 微阵列分析，以研究 RES 处理诱导的全局基因表达谱。使用 Affymetrix 微阵列在 MCF-7 细胞的两种不同 RES 处理下（150μmol/L（IC50）和 250μmol/L 持续 48 小时）测定了 19734 个经过充分鉴定的人类基因的 mRNA 表达水平。在 150μmol/L RES 处理组中，共有 1211 个基因的 mRNA 表达水平发生了两倍或两倍以上的改变（518 个上调和 693 个下调基因）。然而，在 250μmol/L RES 处理组中，有 2412 个基因的表达水平发生了两倍或两倍以上的改变（651 个上调和 1761 个下调基因）。在 RES 处理的两种情况下，几个错配修复、DNA 复制、同源重组（HR）和细胞周期的基因均受到强烈抑制。一致地，我们发现 HR DNA 修复途径的重要复合物 MRN 复合物（MRE11-NBS1-RAD50）的蛋白水平降低。RES 抑制 DNA 修复基因表达的能力有助于克服转化细胞常见的耐药性，并为单独或与其他药物联合使用 RES 进行临床试验提供坚实的基础，以增强治疗效果、降低毒性并克服化疗耐药性。值得注意的是，在 RES 处理后，我们发现两个主要参与 HR 的蛋白质 NBS1 和 MRE11 的蛋白水平降低，这表明 RES 可与抗癌药物联合用于使癌细胞对细胞死亡敏感。
