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BioMed CentralPage 1 of 15(page number not for citation purposes)Journal of Biomedical ScienceOpen AccessResearchApoptosis signal-regulating kinase 1 mediates denbinobin-induced apoptosis in human lung adenocarcinoma cellsChen-Tzu Kuo1, Bing-Chang Chen2, Chung-Chi Yu1, Chih-Ming Weng1, Ming-Jen Hsu1,3, Chien-Chih Chen4, Mei-Chieh Chen5, Che-Ming Teng6, Shiow-Lin Pan6, Mauo-Ying Bien2, Chung-Hung Shih2 and Chien-Huang Lin*1,7,8Address: 1Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC, 2School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC, 3Department of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC, 4National Institute of Chinese Medicine, Taipei, Taiwan, ROC, 5Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC, 6Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC, 7Taipei Medical University-Municipal Wang-Fang Hospital, Taipei, Taiwan, ROC and 8Taipei Medical University-Shuang-Ho Hospital, Taipei County, Taiwan, ROCEmail: Chen-Tzu Kuo - bigkuo7@hotmaol.com; Bing-Chang Chen - bcchen@tmu.edu.tw; Chung-Chi Yu - b8604032@tmu.edu.tw; Chih-Ming Weng - m109090013@tmu.edu.tw; Ming-Jen Hsu - aspirin@tmu.edu.tw; Chien-Chih Chen - ccchen@nricm.edu.tw; Mei-Chieh Chen - mcchen@tmu.edu.tw; Che-Ming Teng - cmteng@ntu.edu.tw; Shiow-Lin Pan - psl0826@ms13.hinet.net; Mauo-Ying Bien - mybien@tmu.edu.tw; Chung-Hung Shih - CHSHIH43@tmu.edu.tw; Chien-Huang Lin* - chlin@tmu.edu.tw* Corresponding author AbstractIn the present study, we explore the role of apoptosis signal-regulating kinase 1 (ASK1) indenbinobin-induced apoptosis in human lung adenocarcinoma (A549) cells. Denbinobin-inducedcell 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 withdenbinobin caused increases in ASK1 activity and reactive oxygen species (ROS) production, andthese effects were inhibited by NAC and GSH. Stimulation of A549 cells with denbinobin causedJNK activation; this effect was markedly inhibited by NAC, GSH, and ASK1DN. Denbinobininduced c-Jun phosphorylation, the formation of an AP-1-specific DNA-protein complex, and Bimexpression. 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 Bimexpression were inhibited by NAC, GSH, SP600125, ASK1DN, JNK1DN, and JNK2DN. Theseresults suggest that denbinobin might activate ASK1 through ROS production to cause JNK/AP-1activation, which in turn induces Bim expression, and ultimately results in A549 cell apoptosis.BackgroundDenbinobin (5-hydroxy-3,7-dimethoxy-1,4-phenan-thraquinone) is purified from several Dendrobium orEphemerantha (Orchidaceae) species, such as D. nobile [1],D. moniliforme [2], and E. lonchophylla [3,4]. It has beenshown that denbinobin possesses many biological effectsPublished: 1 May 2009Journal of Biomedical Science 2009, 16:43doi:10.1186/1423-0127-16-43Received: 26 August 2008Accepted: 1 May 2009This article is available from: http://www.jbiomedsci.com/content/16/1/43© 2009 Kuo et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The cost of publication in Journal of Biomedical Scienceis bourne by the National Science Council, Taiwan.