title: Naphthoquinone derivative PPE8 induces endoplasmic reticulum stress in p53 null H1299 cells.
abstract: 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.
authors: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors: Jin-Cherng
authors: JC
authors: Lien
authors: Department of Health and Nutrition Biotechnology, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan.
authors: Chien-Chun
authors: 0000-0001-8906-4227
authors: CC
authors: Huang
authors: Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan 71703, Taiwan.
authors: Te-Jung
authors: TJ
authors: Lu
authors: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors: Chih-Hsiang
authors: CH
authors: Tseng
authors: Graduate Institute of Marine Biology, National Dong Hwa University, Pingtung 91201, Taiwan ; National Museum of Marine Biology and Aquarium, Pingtung 94450, Taiwan.
authors: Ping-Jyun
authors: PJ
authors: Sung
authors: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors: Hong-Zin
authors: HZ
authors: Lee
authors: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors: Bo-Ying
authors: 0000-0001-5510-6513
authors: BY
authors: Bao
authors: School of Chinese Pharmaceutical Sciences and Medicine Resources, China Medical University, Taichung 40402, Taiwan ; Tsuzuki Institute for Traditional Medicine, China Medical University, Taichung 40402, Taiwan ; Department of Biotechnology, Asia University, Taichung 41354, Taiwan.
authors: Yueh-Hsiung
authors: YH
authors: Kuo
authors: School of Pharmacy, China Medical University, Taichung 40402, Taiwan ; Tsuzuki Institute for Traditional Medicine, China Medical University, Taichung 40402, Taiwan.
authors: Te-Ling
authors: TL
authors: Lu
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005029:Ethylenediamines / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C000601812:3-chloro-2-(N,N-dimethylaminoethylamino)-1,4-naphthoquinone; D000091342:Endoplasmic Reticulum Chaperone BiP; D005029:Ethylenediamines; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D009285:Naphthoquinones; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases