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Oxidative Medicine and Cellular Longevity
Volume 2015 (2015), Article ID 453679, 10 pages
Research Article

Naphthoquinone Derivative PPE8 Induces Endoplasmic Reticulum Stress in p53 Null H1299 Cells

1School of Pharmacy, China Medical University, Taichung 40402, Taiwan
2Department of Health and Nutrition Biotechnology, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan
3Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan
4Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 91201, Taiwan
5National Museum of Marine Biology and Aquarium, Pingtung 94450, Taiwan
6School of Chinese Pharmaceutical Sciences and Medicine Resources, China Medical University, Taichung 40402, Taiwan
7Tsuzuki Institute for Traditional Medicine, China Medical University, Taichung 40402, Taiwan
8Department of Biotechnology, Asia University, Taichung 41354, Taiwan

Received 12 September 2014; Revised 19 December 2014; Accepted 19 December 2014

Academic Editor: Sidhartha D. Ray

Copyright © 2015 Jin-Cherng Lien et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Endoplasmic reticulum (ER) plays a key role in synthesizing secretory proteins and sensing signal function in eukaryotic cells. Responding to calcium disturbance, oxidation state change, or pharmacological agents, ER transmembrane protein, inositol-regulating enzyme 1 (IRE1), senses the stress and triggers downstream signals. Glucose-regulated protein 78 (GRP78) dissociates from IRE1 to assist protein folding and guard against cell death. In prolonged ER stress, IRE1 recruits and activates apoptosis signal-regulating kinase 1 (ASK1) as well as downstream JNK for cell death. Naphthoquinones are widespread natural phenolic compounds. Vitamin K3, a derivative of naphthoquinone, inhibits variant tumor cell growth via oxygen uptake and oxygen stress. We synthesized a novel naphthoquinone derivative PPE8 and evaluated capacity to induce ER stress in p53 null H1299 and p53 wild-type A549 cells. In H1299 cells, PPE8 induced ER enlargement, GRP78 expression, and transient IER1 activation. Activated IRE1 recruited ASK1 for downstream JNK phosphorylation. IRE1 knockdown by siRNA attenuated PPE8-induced JNK phosphorylation and cytotoxicity. Prolonged JNK phosphorylation may be involved in PPE8-induced cytotoxicity. Such results did not arise in A549 cells, but p53 knockdown by siRNA restored PPE8-induced GRP78 expression and JNK phosphorylation. We offer a novel compound to induce ER stress and cytotoxicity in p53-deficient cancer cells, presenting an opportunity for treatment.