The role of the tumor suppressor p53 pathway in the cellular DNA damage response to zinc oxide nanoparticles
The role of the tumor suppressor p53 pathway in the cellular DNA damage response to zinc oxide nanoparticles
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DOI：
10.1016/j.biomaterials.2011.07.036
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发表时间：
2011-11-01
期刊：
影响因子：
14
通讯作者：
Loo, Joachim S. C.
中科院分区：
文献类型：
--
作者：
Ng, Kee Woei;Khoo, Stella P. K.;Loo, Joachim S. C.
在本文中，我们探讨了ZnO纳米颗粒如何与以p53为中心的关键肿瘤抑制途径交叉相互作用，p53是已知最重要的肿瘤抑制因子之一，通过控制细胞凋亡，衰老和细胞周期进程等主要途径来保护细胞免于发展癌症表型。我们发现，p53通路被激活BJ细胞（皮肤成纤维细胞）后，ZnO纳米粒子治疗伴随着细胞数量的减少。这表明，在ZnO纳米颗粒存在下，细胞反应如凋亡需要p53作为朝向程序性细胞死亡的分子主开关。这也表明，在没有强大的p53的细胞中，当受到DNA损伤诱导剂如ZnO纳米颗粒的刺激时，保护性反应可以倾向于致癌。我们在使用内源性表达shRNA敲低p53的相同BJ细胞中观察到这种不稳定的趋势。这些p53敲低的BJ细胞变得对ZnO纳米颗粒诱导的细胞死亡更具抵抗力，并增加了细胞进展。总的来说，我们的研究结果表明，对特定纳米颗粒诱导的细胞毒性和致癌作用的细胞反应不仅取决于特定的纳米颗粒特性，而且（也许更重要的是）靶细胞的内源性遗传，转录组和蛋白质组景观。(C)2011爱思唯尔有限公司版权所有。
In this paper, we explored how ZnO nanoparticles cross-interact with a critical tumor suppressive pathway centered around p53, which is one of the most important known tumor suppressors that protects cells from developing cancer phenotypes through its control over major pathways like apoptosis, senescence and cell cycle progression. We showed that the p53 pathway was activated in BJ cells (skin fibroblasts) upon ZnO nanoparticles treatment with a concomitant decrease in cell numbers. This suggests that cellular responses like apoptosis in the presence of ZnO nanoparticles require p53 as the molecular master switch towards programmed cell death. This also suggests that in cells without robust p53, protective response can be tipped towards carcinogenesis when stimulated by DNA damage inducing agents like ZnO nanoparticles. We observed this precarious tendency in the same BJ cells with p53 knocked down using endogeneous expressing shRNA. These p53 knocked down BJ cells became more resistant to ZnO nanoparticles induced cell death and increased cell progression. Collectively, our results suggest that cellular response towards specific nanoparticle induced cell toxicity and carcinogenesis is not only dependent on specific nanoparticle properties but also (perhaps more importantly) the endogenous genetic, transcriptomic and proteomic landscape of the target cells. (C) 2011 Elsevier Ltd. All rights reserved.