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Nrf-2 transcriptionally activates P21Cip/WAF1 and promotes A549 cell survival against oxidative stress induced by H2O2
Chemico-Biological Interactions ( IF 4.7 ) Pub Date : 2018-02-24 , DOI: 10.1016/j.cbi.2018.02.030
Samarjit Jana , Kartick Patra , Jagannath Jana , Deba Prasad Mandal , Shamee Bhattacharjee

Cancer cells possess elevated ROS coupled with increased levels of antioxidant enzymes which render them resistant against cytotoxic chemotherapies. Therefore, an understanding of the interaction between key molecules involved in stress adaptive mechanisms is important to innovate strategies against cancer cell chemoresistance. Here, the lung adenocarcinoma cell line A549 with constitutively expressed Nrf2 was found to be more tolerant to H2O2 (0.1, 0.2, 0.5 and 1 mM) than normal lung cell line L132 or p53 null lung cancer cell line H1299. Maximum cytoprotection was observed at 0.2 mM H2O2 accompanied by a significant increase in p21, Nrf2 and antioxidant enzymes in A549 cells. The increased p21 expression was independent of p53 but dependent on Nrf2 as evident from qPCR, Western blotting and dual luciferase assays after silencing Nrf-2 and p53 genes. Highly conserved Nrf-2 binding sites were identified in p21 promoter by bioinformatics and homology modeling which was further confirmed by ChIP and reporter assay.



中文翻译:

Nrf-2转录激活P21 Cip / WAF1,并提高A549细胞抵抗H 2 O 2诱导的氧化应激的存活率

癌细胞具有升高的ROS和增加水平的抗氧化酶,使其具有抗细胞毒性化学疗法的能力。因此,了解与压力适应机制有关的关键分子之间的相互作用对于创新抗癌细胞化学耐药性的策略很重要。在此,发现组成型表达Nrf2的肺腺癌细胞系A549比正常的肺细胞系L132或p53无效肺癌细胞系H1299更能耐受H 2 O 2(0.1、0.2、0.5和1 mM)。在0.2 mM H 2 O 2处观察到最大的细胞保护作用伴随着A549细胞中p21,Nrf2和抗氧化酶的显着增加。沉默Nrf-2和p53基因后,从qPCR,Western印迹和双重荧光素酶检测可以明显看出,增加的p21表达独立于p53,但依赖于Nrf2。通过生物信息学和同源性建模,在p21启动子中鉴定出高度保守的Nrf-2结合位点,这一点已通过ChIP和报告基因检测进一步证实。

更新日期:2018-02-24
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