School of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, Singapore.
Biomaterials. 2011 Nov;32(32):8218-25. doi: 10.1016/j.biomaterials.2011.07.036. Epub 2011 Jul 31.
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.
在本文中，我们探讨了 ZnO 纳米粒子如何与以 p53 为中心的关键肿瘤抑制途径相互作用，p53 是已知最重要的肿瘤抑制因子之一，通过其对凋亡、衰老和细胞周期进展等主要途径的控制，保护细胞免受癌症表型的发展。我们表明，在 BJ 细胞（皮肤成纤维细胞）中，ZnO 纳米粒子处理后 p53 途径被激活，同时细胞数量减少。这表明在存在 ZnO 纳米粒子的情况下，细胞凋亡等细胞反应需要 p53 作为向程序性细胞死亡的分子主开关。这也表明，在没有强大 p53 的细胞中，当受到 DNA 损伤诱导剂（如 ZnO 纳米粒子）刺激时，保护性反应可能会向致癌作用倾斜。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 细胞对 ZnO 纳米粒子诱导的细胞死亡和细胞进展的抵抗力增加。总之，我们的结果表明，细胞对特定纳米颗粒诱导的细胞毒性和致癌作用的反应不仅取决于特定纳米颗粒的特性，还取决于（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。
