Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
背景：饮用水受到无机砷污染与不同类型癌症风险的增加有关。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）患者缓解，成功率约为 80%。目前尚未开展全面研究来探讨三氧化二砷抗肿瘤作用的机制和潜在信号通路。
方法：在这里，我们应用系统生物学方法来鉴定与砷诱导的细胞毒性肿瘤细胞反应相关的基因生物标志物。将 NCI-60 肿瘤细胞系panel 来自发育治疗计划（DTP）数据库的 GI50 数据与 14500 个特征明确的人类基因的基线基因表达水平相关联。选择生物标志物进行体外测试，以确定其影响肿瘤对三氧化二砷敏感性的能力。
结果：在肿瘤细胞系panel 暴露于三氧化二砷时，发现 209 个人类基因的基线表达水平与肿瘤细胞系panel 的敏感性之间存在显著关联。这些基因被叠加到蛋白质-蛋白质网络图谱上，以鉴定调节肿瘤细胞对三氧化二砷反应的转录网络。分析显示，核因子红细胞 2 相关因子 2（NRF2）介导的氧化应激反应途径显著富集，在砷抗性肿瘤细胞系中高表达。使用 shRNA 介导的敲低在肿瘤细胞中验证了 NRF2 途径在保护细胞免受砷诱导的细胞杀伤中的作用。
结论：在这项研究中，我们表明 NRF2 通路中的基因表达水平可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，我们证明了 NRF2 缺陷的肿瘤细胞对三氧化二砷更敏感。我们研究的结果将有助于理解细胞中砷诱导细胞毒性的机制，以及三氧化二砷作为癌症治疗中化疗药物的应用增加。
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