Artocarpin, an isoprenyl flavonoid, induces p53-dependent or independent apoptosis via ROS-mediated MAPKs and Akt activation in non-small cell lung cancer cells
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Ming-Horng Tsai1,*, Ju-Fang Liu2,*, Yao-Chang Chiang3,4, Stephen Chu-Sung Hu5,6, Lee-Fen Hsu7, Yu-Ching Lin7,8,9, Zih-Chan Lin10, Hui-Chun Lee1, Mei-Chuan Chen11, Chieh-Liang Huang3, Chiang-Wen Lee4,12,13,14
1Department of Pediatrics, Division of Neonatology and Pediatric Hematology/Oncology, Chang Gung Memorial Hospital, Yunlin, Taiwan
2Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
3Center for Drug Abuse and Addiction, China Medical University Hospital, China Medical University, Taichung, Taiwan
4Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi, Taiwan
5Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
6Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
7Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan
8Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan
9Department of Respiratory Care, Chang Gung University, Taoyuan, Taiwan
10Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
11Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, Taipei, Taiwan
12Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chia-Yi, Taiwan
13Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
14Department of Rehabilitation, Chang Gung Memorial Hospital, Chia-Yi 61363, Taiwan
*These authors contributed equally to this work
Chiang-Wen Lee, email: firstname.lastname@example.org
Keywords: artocarpin, pro-oxidation, lung cancer, p53, apoptosis
Received: June 15, 2016 Accepted: February 27, 2017 Published: March 09, 2017
Artocarpin has been shown to exhibit cytotoxic effects on different cancer cells, including non-small cell lung carcinoma (NSCLC, A549). However, the underlying mechanisms remain unclear. Here, we explore both p53-dependent and independent apoptosis pathways in artocarpin-treated NSCLC cells. Our results showed that artocarpin rapidly induced activation of cellular protein kinases including Erk1/2, p38 and AktS473. Inhibition of these protein kinases prevented artocarpin-induced cell death. Moreover, artocarpin-induced phosphorylation of these protein kinases and apoptosis were mediated by induction of reactive oxygen species (ROS), as pretreatment with NAC (a ROS scavenger) and Apocynin (a Nox-2 inhibitor) blocked these events. Similarly, transient transfection of p47Phox or p91Phox siRNA attenuated artocarpin-induced NADPH oxidase activity and cell death. In addition, p53 dependent apoptotic proteins including PUMA, cytochrome c, Apaf-1 and caspase 3 were activated by artocarpin, and these effects can be abolished by antioxidants, MAPK inhibitors (U0126 and SB202190), but not by PI3K inhibitor (LY294002). Furthermore, we found that artocarpin-induced Akt phosphorylation led to increased NF-κB activity, which may act as an upstream regulator in the c-Myc and Noxa pathway. Therefore, we propose that enhancement of both ERK/ p38/ p53-dependent or independent AktS473/NF-κB/c-Myc/Noxa cascade by Nox-derived ROS generation plays an important role in artocarpin-induced apoptosis in NSCLC cells.
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