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Apoptosis signal-regulating kinase 1 mediates denbinobin-induced apoptosis in human lung adenocarcinoma cells |
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| Authors: | Chen-Tzu Kuo Bing-Chang Chen Chung-Chi Yu Chih-Ming Weng Ming-Jen Hsu Chien-Chih Chen Mei-Chieh Chen Che-Ming Teng Shiow-Lin Pan Mauo-Ying Bien Chung-Hung Shih Chien-Huang Lin |
| Affiliation: | 1. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC 2. School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC 3. Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC 4. National Institute of Chinese Medicine, Taipei, Taiwan, ROC 5. Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC 6. Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC 7. Taipei Medical University-Municipal Wang-Fang Hospital, Taipei, Taiwan, ROC 8. Taipei Medical University-Shuang-Ho Hospital, Taipei County, Taiwan, ROC |
| Abstract: | In the present study, we explore the role of apoptosis signal-regulating kinase 1 (ASK1) in denbinobin-induced apoptosis in human lung adenocarcinoma (A549) cells. Denbinobin-induced cell apoptosis was attenuated by an ASK1 dominant-negative mutant (ASK1DN), two antioxidants (N-acetyl-L-cysteine (NAC) and glutathione (GSH)), a c-Jun N-terminal kinase (JNK) inhibitor (SP600125), and an activator protein-1 (AP-1) inhibitor (curcumin). Treatment of A549 cells with denbinobin caused increases in ASK1 activity and reactive oxygen species (ROS) production, and these effects were inhibited by NAC and GSH. Stimulation of A549 cells with denbinobin caused JNK activation; this effect was markedly inhibited by NAC, GSH, and ASK1DN. Denbinobin induced c-Jun phosphorylation, the formation of an AP-1-specific DNA-protein complex, and Bim expression. Bim knockdown using a bim short interfering RNA strategy also reduced denbinobin-induced A549 cell apoptosis. The denbinobin-mediated increases in c-Jun phosphorylation and Bim expression were inhibited by NAC, GSH, SP600125, ASK1DN, JNK1DN, and JNK2DN. These results suggest that denbinobin might activate ASK1 through ROS production to cause JNK/AP-1 activation, which in turn induces Bim expression, and ultimately results in A549 cell apoptosis. |
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