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

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

  • Oncotarget. 2017 Apr 25;8(17):28342-28358. doi: 10.18632/oncotarget.16058.
Ming-Horng Tsai 1,  Ju-Fang Liu 2,  Yao-Chang Chiang 3 4,  Stephen Chu-Sung Hu 5 6,  Lee-Fen Hsu 7,  Yu-Ching Lin 7 8 9,  Zih-Chan Lin 10,  Hui-Chun Lee 1,  Mei-Chuan Chen 11,  Chieh-Liang Huang 3,  Chiang-Wen Lee 4 12 13
Affiliations

Affiliations

  • 1 Department of Pediatrics, Division of Neonatology and Pediatric Hematology/Oncology, Chang Gung Memorial Hospital, Yunlin, Taiwan.
  • 2 Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
  • 3 Center for Drug Abuse and Addiction, China Medical University Hospital, China Medical University, Taichung, Taiwan.
  • 4 Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi, Taiwan.
  • 5 Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  • 6 Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
  • 7 Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan.
  • 8 Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
  • 9 Department of Respiratory Care, Chang Gung University, Taoyuan, Taiwan.
  • 10 Graduate Institute of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan.
  • 11 Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 12 Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chia-Yi, Taiwan.
  • 13 Research 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.
PMID: 28423703 DOI: 10.18632/oncotarget.16058
Abstract

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.

Keywords

apoptosis; artocarpin; lung cancer; p53; pro-oxidation.

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