4-NQO induces apoptosis via p53-dependent mitochondrial signaling pathway.
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.
Han
Hongbing
H
Laboratory of Animal Genetics and Breeding, Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100094, PR China.
Pan
Qiuzhen
Q
Zhang
Baolu
B
Li
Jia
J
Deng
Xuemei
X
Lian
Zhengxing
Z
Li
Ning
N
D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity; D053143:Caspase 2 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002461:Cell Line, Transformed; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007624:KB Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics
C493956:CDKN1A protein, human; D002273:Carcinogens; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D015112:4-Nitroquinoline-1-oxide; D053143:Caspase 2; D053453:Caspase 9