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Titanium dioxide nanoparticles induce mitochondria-associated apoptosis in HepG2 cells

机译：二氧化钛纳米颗粒诱导HepG2细胞中的线粒体相关凋亡

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摘要

Widespread applications of nanosized materials over the past decade have prompted investigations of desirable properties and potential hazards to humans and the environment. Titanium dioxide (TiO2) nanoparticles are one of the most widely used nanoparticles. To investigate the effect of biological functions induced by TiO2 nanoparticles (10 nm: TiO2 NPs) on human liver cell lines, normal liver cell line L02 and hepatoma cell line HepG2 were co-cultured with exogenous TiO2 NPs. Cell growth and proliferation, cell cycle, and the apoptosis rate were analyzed. The effects of TiO2 NPs on the expression levels of apoptosis-associated protein caspase-3 and the membrane channel protein ENaC and caspase-3/7 activity were determined. Moreover, the influence of TiO2 NPs on the expression levels of the mitochondria-related proteins SIRT3, VDAC1, and ACSS1, the mitochondrial membrane potential and the ADP/ATP ratio were also examined. Our results revealed that TiO2 NPs inhibited the growth and proliferation of HepG2 cells, suppressed the S phase of cell cycling, and induced apoptosis of HepG2 cells. Following an increase in concentration, the inhibitory effect induced by TiO2 NPs on proliferation and cell cycle was more evident, and the apoptosis rate increased in a significant concentration-dependent manner, whereas there was no significant effect on the growth, proliferation, apoptosis, and cell cycle of L02 cells. In addition, the results of western blot showed that in HepG2 cells, TiO2 NPs upregulated the expressions of the apoptosis-related protein caspase-3 and the membrane channel protein ENaC in a concentration-dependent manner. However, in L02 cells, there was no significant difference in the expression levels of caspase-3 or ENaC. Furthermore, TiO2 NPs induced depolarization of the mitochondrial membrane, upregulated the expression levels of the mitochondria-related proteins SIRT3 and VDAC1, and downregulated the expression level of the key respiratory chain protein ACSS1 in HepG2 cells. However, in L02 cells, the expressions of SIRT3, VDAC1, and ACSS1 exhibited no clear change. The apoptosis of HepG2 cells induced by TiO2 NPs may be achieved by regulating intracellular osmotic pressure; moreover, upregulating the expression of the channel protein ENaC or the mitochondrial porin VDAC1 and depolarizing the mitochondrial membrane of HepG2 cells resulted in the loss of Cyt-c and ATP and further activated caspase-3. To further confirm the above results, a nude mouse xenograft model was employed. After a certain period of treatment with TiO2 NPs, the nude mice were sacrificed, tumors were removed, and the expression of related proteins was detected. Immunohistochemistry and western blot results showed that the expressions of the proteins VDAC1 and SIRT3 were clearly upregulated in tissues treated to TiO2 NPs, whereas the expression of ACSS1 was downregulated. The results were consistent with the above in vitro results. All the above results confirmed that TiO2 NPs can act as a safe antitumor agent.
机译：纳米材料在过去十年中的广泛应用促使对人类和环境的理想性质和潜在危害的研究。二氧化钛（TiO 2）纳米颗粒是最广泛使用的纳米颗粒之一。为了探讨TiO2纳米颗粒（10nm：TiO 2 NPS）对人肝细胞系诱导的生物功能的影响，用外源TiO 2 NP共培养正常肝细胞系L02和肝癌细胞系Hepg2。分析了细胞生长和增殖，细胞周期和凋亡率。测定了TiO2NP对凋亡相关蛋白质caspase-3表达水平和膜通道蛋白烯丙烷和胱天蛋白-3 / 7活性的影响。此外，还研究了TiO2 NP对线粒体相关蛋白SIRT3，VDAC1和ACSS1的表达水平的影响，对线粒体膜电位和ADP / ATP比率进行了影响。我们的研究结果表明，TiO2 NPS抑制了HepG2细胞的生长和增殖，抑制了细胞循环的S期，并诱导了HepG2细胞的凋亡。在浓度增加之后，TiO2 NPS对增殖和细胞周期产生的抑制作用更明显，并且细胞凋亡率以显着的浓度依赖性方式增加，而对生长，增殖，细胞凋亡没有显着影响。 L02细胞的细胞周期。此外，Western印迹的结果表明，在HepG2细胞中，TiO2 NP以浓度依赖性方式上调凋亡相关蛋白质caspase-3和膜通道蛋白enac的表达。然而，在L02细胞中，Caspase-3或ENAC的表达水平没有显着差异。此外，TiO2 NPS诱导线粒体膜的去极化，上调了线粒体相关蛋白SIRT3和Vdac1的表达水平，并下调了HepG2细胞中的关键呼吸链蛋白ACSS1的表达水平。然而，在L02细胞中，SIRT3，VDAC1和ACSS1的表达没有明确变化。通过调节细胞内渗透压可以实现由TiO2 NPS诱导的HepG2细胞的凋亡;此外，上调通道蛋白enac或线粒体孔隙vdac1的表达并去极化HepG2细胞的线粒体膜，导致Cyt-C和ATP的损失以及进一步活化的Caspase-3。为了进一步证实上述结果，采用裸鼠异种移植模型。在用TiO2 NPS进行一定时期后，处死裸鼠，除去肿瘤，检测肿瘤的表达。免疫组织化学和蛋白质印迹结果表明，在处理到TiO2 NP的组织中，蛋白质Vdac1和Sirt3的表达明显上调，而ACSS1的表达被下调。结果与上述体外结果一致。所有上述结果证实，TiO2 NPS可以充当安全的抗肿瘤剂。

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  • 来源
    《RSC Advances》 |2018年第55期|共13页
  • 作者

    Xia Zhenglin; He Jingliang; Li Bowei; He Ke; Yang Wenbing; Chen Xiaoxun; Zhang Jinqian; Xiang Guoan;

  • 作者单位

    Southern Med Univ Dept Gen Surg Guangdong Prov Gen Hosp 2 Guangzhou 510515 Guangdong Peoples R China;

    Guangzhou Univ Chinese Med Shunde Hosp Foshan 528300 Peoples R China;

    Southern Med Univ Dept Gen Surg Guangdong Prov Gen Hosp 2 Guangzhou 510515 Guangdong Peoples R China;

    Southern Med Univ Dept Gen Surg Guangdong Prov Gen Hosp 2 Guangzhou 510515 Guangdong Peoples R China;

    Xi An Jiao Tong Univ Affiliated Hosp 2 Dept Gen Surg Xian 710004 Shaanxi Peoples R China;

    Guigang City Peoples Hosp Dept Gastrointestinal Surg Guigang 537100 Guangxi Peoples R China;

    Southern Med Univ Dept Lab Med Guangdong Prov Gen Hosp 2 Guangzhou 510515 Guangdong Peoples R China;

    Southern Med Univ Dept Gen Surg Guangdong Prov Gen Hosp 2 Guangzhou 510515 Guangdong Peoples R China;

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