Research Papers:

This article has been corrected. Correction in: Oncotarget. 2019; 10:3430.

Artocarpin, an isoprenyl flavonoid, induces p53-dependent or independent apoptosis via ROS-mediated MAPKs and Akt activation in non-small cell lung cancer cells

Ming-Horng Tsai, Ju-Fang Liu, Yao-Chang Chiang, Stephen Chu-Sung Hu, Lee-Fen Hsu, Yu-Ching Lin, Zih-Chan Lin, Hui-Chun Lee, Mei-Chuan Chen, Chieh-Liang Huang and Chiang-Wen Lee _

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Oncotarget. 2017; 8:28342-28358. https://doi.org/10.18632/oncotarget.16058

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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

Correspondence to:

Chiang-Wen Lee, email: cwlee@mail.cgust.edu.tw

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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