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Titanium dioxide nanoparticles induce mitochondria-associated apoptosis in HepG2 cells

机译：二氧化钛纳米颗粒在HepG2细胞中诱导线粒体相关凋亡

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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 (TiO _(2) ) nanoparticles are one of the most widely used nanoparticles. To investigate the effect of biological functions induced by TiO _(2) nanoparticles (10 nm: TiO _(2) NPs) on human liver cell lines, normal liver cell line L02 and hepatoma cell line HepG2 were co-cultured with exogenous TiO _(2) NPs. Cell growth and proliferation, cell cycle, and the apoptosis rate were analyzed. The effects of TiO _(2) NPs on the expression levels of apoptosis-associated protein caspase-3 and the membrane channel protein αENaC and caspase-3/7 activity were determined. Moreover, the influence of TiO _(2) 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 TiO _(2) 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 TiO _(2) 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, TiO _(2) NPs upregulated the expressions of the apoptosis-related protein caspase-3 and the membrane channel protein αENaC in a concentration-dependent manner. However, in L02 cells, there was no significant difference in the expression levels of caspase-3 or αENaC. Furthermore, TiO _(2) 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 TiO _(2) NPs may be achieved by regulating intracellular osmotic pressure; moreover, upregulating the expression of the channel protein αENaC 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 TiO _(2) 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 TiO _(2) NPs, whereas the expression of ACSS1 was downregulated. The results were consistent with the above in vitro results. All the above results confirmed that TiO _(2) NPs can act as a safe antitumor agent.
机译：在过去的十年中，纳米材料的广泛应用促使人们对理想的特性以及对人类和环境的潜在危害进行了研究。二氧化钛（TiO_（2））纳米粒子是使用最广泛的纳米粒子之一。为了研究TiO _（2）纳米粒子（10 nm：TiO _（2）NPs）诱导的生物学功能对人肝细胞系的影响，将正常肝细胞L02和肝癌细胞系HepG2与外源TiO _共培养。 （2）NP。分析细胞的生长和增殖，细胞周期和凋亡率。确定了TiO_（2）NPs对凋亡相关蛋白caspase-3表达水平，膜通道蛋白αENaC和caspase-3 / 7活性的影响。此外，还检测了TiO_（2）NPs对线粒体相关蛋白SIRT3，VDAC1和ACSS1表达水平，线粒体膜电位和ADP / ATP比的影响。我们的研究结果表明TiO _（2）NPs抑制HepG2细胞的生长和增殖，抑制细胞周期的S期，并诱导HepG2细胞凋亡。随着浓度的增加，TiO _（2）NPs诱导的对增殖和细胞周期的抑制作用更加明显，并且凋亡率以明显的浓度依赖性方式增加，而对生长，增殖没有显着影响L02细胞的凋亡，凋亡和细胞周期。此外，蛋白质印迹法的结果表明，在HepG2细胞中，TiO_（2）NPs以浓度依赖的方式上调凋亡相关蛋白caspase-3和膜通道蛋白αENaC的表达。然而，在L02细胞中，caspase-3或αENaC的表达水平没有显着差异。此外，TiO_（2）NPs诱导线粒体膜去极化，上调线粒体相关蛋白SIRT3和VDAC1的表达水平，并下调关键呼吸链蛋白ACSS1在HepG2细胞中的表达水平。然而，在L02细胞中，SIRT3，VDAC1和ACSS1的表达没有明显变化。 TiO_（2）NPs诱导HepG2细胞凋亡可能是通过调节细胞内渗透压来实现的。此外，上调通道蛋白αENaC或线粒体孔蛋白VDAC1的表达并使HepG2细胞的线粒体膜去极化导致Cyt-c和ATP的丢失，并进一步激活了caspase-3。为了进一步证实上述结果，采用了裸鼠异种移植模型。用TiO _（2）NPs治疗一定时间后，处死裸鼠，切除肿瘤，并检测相关蛋白的表达。免疫组织化学和蛋白质印迹结果表明，在用TiO _（2）NPs处理的组织中，蛋白VDAC1和SIRT3的表达明显上调，而ACSS1的表达下调。结果与上述体外结果一致。以上所有结果证实了TiO_（2）NPs可以作为安全的抗肿瘤剂。

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