Han Hongbing, Pan Qiuzhen, Zhang Baolu, Li Jia, Deng Xuemei, Lian Zhengxing, Li Ning
Laboratory of Animal Genetics and Breeding, Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100094, PR China.
Toxicology. 2007 Feb 12;230(2-3):151-63. doi: 10.1016/j.tox.2006.11.045. Epub 2006 Nov 15.
4-Nitroquinoline N-oxide (4-NQO) as an UV-mimetic agent leading to DNA damage is a potent mutagen and carcinogen, and can induce apoptosis in various types of cells. However, the mechanism of apoptosis induced by 4-NQO is still not quite clarified. In this study we found that 4-NQO could not only induce apoptosis in KB cells, but also caused considerable damage to the mitochondrial membrane. Therefore, we inferred that 4-NQO might induce apoptosis through the mitochondrial signaling pathway resulting from DNA damage. Further investigation showed that the apoptosis induced by 4-NQO was p53-dependent. Furthermore, the expression levels of bax and bcl-2, closely related to mitochondrial signaling pathway, were up- and down-regulated, respectively. Meanwhile, the activity of caspase-9 and -3, lying in downstream of mitochondrial, was also enhanced. At the same time, the expression level of p21 also was increased by 4-NQO exposure, leading to the cell cycle arrested in G(1) phase. The results indicated that 4-NQO arrested cell cycle in G(1) phase, thus allowing enough time for DNA repair; on the other hand, if the cellular DNA were not repaired, apoptosis may follow through the p53-dependent mitochondrial signaling pathway, and mechanism of apoptosis induced by 4-NQO is not exactly the same that induced by UV radiation, as the later induces apoptosis through death receptors and mitochondrial signaling pathway.
4-硝基喹啉-N-氧化物（4-NQO）作为一种可导致DNA损伤的紫外线模拟剂，是一种强效诱变剂和致癌物，可诱导多种类型细胞发生凋亡。然而，4-NQO诱导凋亡的机制仍未完全阐明。在本研究中，我们发现4-NQO不仅能诱导KB细胞凋亡，还会对线粒体膜造成相当大的损伤。因此，我们推断4-NQO可能通过DNA损伤引发的线粒体信号通路诱导凋亡。进一步研究表明，4-NQO诱导的凋亡依赖于p53。此外，与线粒体信号通路密切相关的bax和bcl-2的表达水平分别上调和下调。同时，位于线粒体下游的caspase-9和-3的活性也增强。同时，4-NQO暴露还使p21的表达水平升高，导致细胞周期停滞在G(1)期。结果表明，4-NQO使细胞周期停滞在G(1)期，从而为DNA修复留出足够时间；另一方面，如果细胞DNA未得到修复，可能会通过p53依赖的线粒体信号通路引发凋亡，并且4-NQO诱导凋亡的机制与紫外线辐射诱导凋亡的机制并不完全相同，因为后者通过死亡受体和线粒体信号通路诱导凋亡。
