RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy.
RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy.
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DOI：
10.1158/0008-5472.can-08-1401
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Biswal S
中科院分区：
文献类型：
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作者：
Singh A;Boldin-Adamsky S;Thimmulappa RK;Rath SK;Ashush H;Coulter J;Blackford A;Goodman SN;Bunz F;Watson WH;Gabrielson E;Feinstein E;Biswal S
核因子红细胞-2相关因子-2（Nrf 2）是一种氧化还原敏感的转录因子，调节亲电体和异生物质解毒酶和外排蛋白的表达，其赋予正常细胞中抗氧化应激和凋亡的细胞保护作用。Nrf 2抑制剂Kelch样ECH相关蛋白（Keap 1）的功能突变缺失导致非小细胞肺癌（NSCLC）中Nrf 2功能的组成性激活。在这项研究中，我们证明，在肺癌细胞中的Nrf 2的组成性激活促进致瘤性，并有助于通过上调谷胱甘肽，硫氧还蛋白和药物外排途径参与解毒的亲电体和广谱药物的化疗耐药性。RNAi介导的肺癌细胞中Nrf 2表达的降低诱导活性氧的产生，抑制肿瘤生长，并导致体外和体内对化疗药物诱导的细胞死亡的敏感性增加。使用裸siRNA双链体与卡铂组合抑制Nrf 2表达显著抑制肺癌皮下模型中的肿瘤生长。因此，靶向肺癌中的Nrf 2活性，特别是那些具有Keap 1突变的肺癌，可能是抑制肿瘤生长和规避化疗耐药性的有希望的策略。
Nuclear factor erythroid-2 related factor-2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of electrophile and xenobiotic detoxification enzymes and efflux proteins, which confer cytoprotection against oxidative stress and apoptosis in normal cells. Loss of function mutations in the Nrf2 inhibitor, Kelch-like ECH-associated protein (Keap1), results in constitutive activation of Nrf2 function in non-small-cell lung cancer (NSCLC). In this study, we demonstrate that constitutive activation of Nrf2 in lung cancer cells promotes tumorigenicity and contributes to chemoresistance by upregulation of glutathione, thioredoxin and the drug efflux pathways involved in detoxification of electrophiles and broad spectrum of drugs. RNAi-mediated reduction of Nrf2 expression in lung cancer cells induces generation of reactive oxygen species, suppresses tumor growth and results in increased sensitivity to chemotherapeutic drug induced cell death in vitro and in vivo. Inhibiting Nrf2 expression using naked siRNA duplexes in combination with carboplatin significantly inhibits tumor growth in a subcutaneous model of lung cancer. Thus, targeting Nrf2 activity in lung cancers, particularly those with Keap1 mutations, could be a promising strategy to inhibit tumor growth and circumvent chemoresistance.