Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs
Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs
复制标题
木犀草素抑制 Nrf2，导致 Nrf2/ARE 通路负调节，并使人肺癌 A549 细胞对治疗药物敏感
DOI：
10.1016/j.freeradbiomed.2011.03.008
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发表时间：
2011-06-01
影响因子：
7.4
通讯作者：
Wang, Xiu Jun
中科院分区：
文献类型：
--
作者：
Tang, Xiuwen;Wang, Hongyan;Wang, Xiu Jun
核因子红细胞2相关因子2（Nrf2）是一种氧化还原敏感的转录因子，调节一系列细胞保护基因的表达。许多肿瘤中的组成型Nrf2活化增强细胞存活和对抗癌药物的抗性。使用基于细胞的ARE报告基因测定，我们发现类黄酮毛地黄黄酮是一种有效的Nrf2抑制剂。木犀草素抑制ARE驱动的基因表达氧化还原独立。在非小细胞肺癌A549细胞中，具有组成型活性Nrf2，木犀草素引起Nrf2在mRNA和蛋白水平上的显着减少，导致Nrf2与战神的结合减少，ARE驱动基因的下调，以及还原型谷胱甘肽的耗尽。用放线菌素0阻断转录后，1 μ M木樨草素在30分钟内使Nrf2 mRNA水平降低34%，表明其在加速Nrf2 mRNA周转中的作用。在生理浓度下，毛地黄黄酮显著地使A549细胞对抗癌药物奥沙利铂、博来霉素和阿霉素敏感。然而，使用siRNA敲低Nrf2基本上消除了类黄酮诱导的敏感性，这意味着抑制Nrf2对其活性的重要性。我们的研究表明，Nrf2抑制剂可以增强癌细胞对化疗药物的反应性，并表明木犀草素作为天然增敏剂在化疗中的潜在应用。(C)2011 Elsevier Inc. All rights reserved.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor regulating the expression of a battery of cytoprotective genes. Constitutive Nrf2 activation in many tumors enhances cell survival and resistance to anticancer drugs. Using a cell-based ARE-reporter assay we discovered that the flavonoid luteolin is a potent Nrf2 inhibitor. Luteolin inhibited ARE-driven gene expression redox-independently. In non-small-cell lung cancer A549 cells, which possess constitutively active Nrf2, luteolin elicited a dramatic reduction in Nrf2 at both the mRNA and the protein levels, leading to decreased Nrf2 binding to AREs, down-regulation of ARE-driven genes, and depletion of reduced glutathione. After transcription was blocked with actinomycin 0, 1 mu M luteolin decreased the Nrf2 mRNA level by 34% in 30 min, indicating its role in accelerating Nrf2 mRNA turnover. At physiological concentrations, luteolin significantly sensitized A549 cells to the anticancer drugs oxaliplatin, bleomycin, and doxorubicin. However, knockdown of Nrf2 using siRNA essentially abolished the induced sensitivity by the flavonoid, implying the importance of inhibiting Nrf2 for its activity. Our study demonstrates that an Nrf2 inhibitor can enhance the responsiveness of cancer cells to chemotherapeutic drugs and indicates the potential application of luteolin as a natural sensitizer in chemotherapy. (C) 2011 Elsevier Inc. All rights reserved.