The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel.
The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel.
复制标题
DOI：
10.1186/1755-8794-3-37
复制
发表时间：
2010-08-13
影响因子：
2.7
通讯作者：
Fry RC
中科院分区：
文献类型：
--
作者：
Liu Q;Zhang H;Smeester L;Zou F;Kesic M;Jaspers I;Pi J;Fry RC
饮用被无机砷污染的水会增加患不同类型癌症的风险。矛盾的是，三氧化二砷也可用于诱导急性早幼粒细胞白血病（APL）患者的缓解，成功率约为80%。关于三氧化二砷抗肿瘤作用机制和潜在信号通路的全面研究尚未开展。在这里，我们应用了系统生物学的方法来鉴定基因生物标志物的肿瘤细胞对砷诱导的细胞毒性反应的基础。14,500个特征良好的人类基因的基线基因表达水平与来自发育治疗计划（DTP）数据库的NCI-60肿瘤细胞系面板的GI50数据相关。选定的生物标志物在体外测试影响肿瘤对三氧化二砷易感性的能力。发现209个人类基因的基线表达水平与肿瘤细胞系暴露于三氧化二砷后的敏感性之间存在显著关联。这些基因被叠加到蛋白质-蛋白质网络图上，以确定调节肿瘤细胞对三氧化二砷反应的转录网络。结果表明，高表达的核因子红系2相关因子2 （NRF2）介导的氧化应激反应通路在抗砷肿瘤细胞系中显著富集。通过shrna介导的敲除，NRF2通路在保护细胞免受砷诱导的细胞杀伤中的作用在肿瘤细胞中得到了验证。在这项研究中，我们发现NRF2通路中基因的表达水平可以作为肿瘤细胞对三氧化二砷反应的潜在基因生物标志物。重要的是，我们证明缺乏NRF2的肿瘤细胞对三氧化二砷的敏感性增加。我们的研究结果将有助于理解砷诱导细胞毒性的机制，以及三氧化二砷作为化疗药物在癌症治疗中的适用性。
Drinking water contaminated with inorganic arsenic is associated with increased risk for different types of cancer. Paradoxically, arsenic trioxide can also be used to induce remission in patients with acute promyelocytic leukemia (APL) with a success rate of approximately 80%. A comprehensive study examining the mechanisms and potential signaling pathways contributing to the anti-tumor properties of arsenic trioxide has not been carried out. Here we applied a systems biology approach to identify gene biomarkers that underlie tumor cell responses to arsenic-induced cytotoxicity. The baseline gene expression levels of 14,500 well characterized human genes were associated with the GI50 data of the NCI-60 tumor cell line panel from the developmental therapeutics program (DTP) database. Selected biomarkers were tested in vitro for the ability to influence tumor susceptibility to arsenic trioxide. A significant association was found between the baseline expression levels of 209 human genes and the sensitivity of the tumor cell line panel upon exposure to arsenic trioxide. These genes were overlayed onto protein-protein network maps to identify transcriptional networks that modulate tumor cell responses to arsenic trioxide. The analysis revealed a significant enrichment for the oxidative stress response pathway mediated by nuclear factor erythroid 2-related factor 2 (NRF2) with high expression in arsenic resistant tumor cell lines. The role of the NRF2 pathway in protecting cells against arsenic-induced cell killing was validated in tumor cells using shRNA-mediated knock-down. In this study, we show that the expression level of genes in the NRF2 pathway serve as potential gene biomarkers of tumor cell responses to arsenic trioxide. Importantly, we demonstrate that tumor cells that are deficient for NRF2 display increased sensitivity to arsenic trioxide. The results of our study will be useful in understanding the mechanism of arsenic-induced cytotoxicity in cells, as well as the increased applicability of arsenic trioxide as a chemotherapeutic agent in cancer treatment.
登录
查看更多内容
影响因子：
4.5
作者：
Fry RC;Navasumrit P;Valiathan C;Svensson JP;Hogan BJ;Luo M;Bhattacharya S;Kandjanapa K;Soontararuks S;Nookabkaew S;Mahidol C;Ruchirawat M;Samson LD
通讯作者：
Samson LD
影响因子：
3.8
作者：
Hwang, Bor-Jang;Utti, Charles;Steinberg, Mark
通讯作者：
Steinberg, Mark
影响因子：
10.4
作者：
Jardim MJ;Fry RC;Jaspers I;Dailey L;Diaz-Sanchez D
通讯作者：
Diaz-Sanchez D
影响因子：
9.3
作者：
Lau, Alexandria;Villeneuve, Nicole F.;Sun, Zheng;Wong, Pak Kin;Zhang, Donna D.
通讯作者：
Zhang, Donna D.
影响因子：
4.8
作者：
Kühnel, F;Zender, L;Kubicka, S
通讯作者：
Kubicka, S