Ionizing radiation activates the Nrf2 antioxidant response.
Ionizing radiation activates the Nrf2 antioxidant response.
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DOI：
10.1158/0008-5472.can-10-0171
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发表时间：
2010-11-01
期刊：
影响因子：
11.2
通讯作者：
McBride WH
中科院分区：
文献类型：
--
作者：
McDonald JT;Kim K;Norris AJ;Vlashi E;Phillips TM;Lagadec C;Della Donna L;Ratikan J;Szelag H;Hlatky L;McBride WH
转录因子Nrf2与抗氧化剂DNA反应元件(ARE)结合，激活重要的细胞保护防御系统。最近，几种类型的癌症被证明过度表达Nrf2，但它在细胞对放射治疗的反应中的作用尚未完全确定。在这项研究中，我们报告了2-8Gy单剂量电离辐射以剂量依赖的方式激活乳腺癌细胞中Are依赖的转录，但仅在延迟5天后。临床上与辐射相关的每日剂量分数也增加了ARE依赖的转录，但仅在5天后再次增加。下游激活发生在Nrf2-ARE依赖的基因和蛋白质标记物，如血红素加氧酶-1，而Nrf2缺失的成纤维细胞不能进行这些反应。与野生型成纤维细胞相比，NRF2缺乏的成纤维细胞具有相对较高的基础活性氧水平，在辐射暴露后五天显著增加。此外，体外克隆存活分析和体内亚致死性全身照射试验表明，Nrf2缺失增加了辐射敏感性，而Nrf2诱导的药物不增加辐射抗性。我们的结果表明，Nrf2-ARE通路对于维持对辐射的抵抗是重要的，但它只在特定情况下作为第二级抗氧化剂适应性反应系统被辐射激活，包括那些在标准临床剂量分级放射治疗中可能与肿瘤反应高度相关的环境。
The transcription factor Nrf2 binds the antioxidant DNA response element (ARE) to activate important cellular cytoprotective defense systems. Recently several types of cancers have been shown to overexpress Nrf2, but its role in the cellular response to radiation therapy has yet to be fully determined. In this study, we report that single doses of ionizing radiation from 2-8Gy activate ARE-dependent transcription in breast cancer cells in a dose-dependent manner, but only after a delay of 5 days. Clinically relevant daily dose fractions of radiation also increased ARE-dependent transcription, but again only after 5 days. Downstream activation occurred of Nrf2-ARE-dependent gene and protein markers, such as heme oxygenase-1, whereas Nrf2-deficient fibroblasts were incapable of these responses. Compared to wild-type fibroblasts, Nrf2-deficient fibroblasts had relatively high basal levels of reactive oxygen species that increased greatly five days after radiation exposure. Further, in vitro clonogenic survival assays and in vivo sublethal whole body irradiation tests demonstrated that Nrf2 deletion increased radiation sensitivity, whereas Nrf2-inducing drugs did not increase radioresistance. Our results indicate that the Nrf2-ARE pathway is important to maintain resistance to irradiation, but that it operates as a second-tier antioxidant adaptive response system activated by radiation only under specific circumstances, including those that may be highly relevant to tumor response during standard clinical dose-fractionated radiation therapy.