title: Dehydroeffusol inhibits gastric cancer cell growth and tumorigenicity by selectively inducing tumor-suppressive endoplasmic reticulum stress and a moderate apoptosis.
abstract: Gastric cancer is ranked as the third leading cause of cancer-related death in the world. Although extensive efforts have been made in recent decades to treat gastric cancer with various anticancer drugs, effective anti-gastric cancer therapeutics to cure the disease are still lacking in the clinics. Therefore, potent novel anti-gastric cancer drugs are greatly needed. In this study, we explored a novel anti-gastric cancer agent from a medicinal herb named Juncus effusus and found that the active component dehydroeffusol (DHE), a small molecular phenanthrene, effectively inhibited gastric cancer cell proliferation and tumorigenesis by inducing tumor suppressive endoplasmic reticulum (ER) stress and by triggering moderate apoptosis. Mechanistic studies revealed that DHE selectively activated the intracellular tumor suppressive stress response by promoting the overexpression of the key ER stress marker DNA damage-inducible transcript 3 (DDIT3), through upregulation of activating transcription factor 4 (ATF4). Concurrently, DHE suppressed the expression of the cell survival and ER stress marker glucose regulated protein of molecular mass 78 (GRP78) via downregulation of the transcription factor ATF6. In addition, DHE markedly activated the stress response signaling pathway MEKK4-MKK3/6-p38-DDIT3, but significantly inhibited ERK signaling. Our data suggest that DHE inhibits gastric cancer cell growth and tumorigenicity through selectively inducing a robust tumor suppressive ER stress response and a moderate apoptosis response. Therefore, DHE may provide a novel drug candidate for further development of potential anti-gastric cancer therapeutics.
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, School of Biology and Basic Medical Sciences, Suzhou Institute of Chinese Materia Medica, 2011 Collaborative Innovation Center of Hematology, University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, School of Biology and Basic Medical Sciences, Suzhou Institute of Chinese Materia Medica, 2011 Collaborative Innovation Center of Hematology, University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, PR China. Electronic address: hhy2469@126.com.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Han
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, School of Biology and Basic Medical Sciences, Suzhou Institute of Chinese Materia Medica, 2011 Collaborative Innovation Center of Hematology, University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, PR China.
authors.forename: Shilong
authors.initials: S
authors.lastname: Fu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, School of Biology and Basic Medical Sciences, Suzhou Institute of Chinese Materia Medica, 2011 Collaborative Innovation Center of Hematology, University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, School of Biology and Basic Medical Sciences, Suzhou Institute of Chinese Materia Medica, 2011 Collaborative Innovation Center of Hematology, University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, PR China.
authors.forename: Zhenlun
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, School of Biology and Basic Medical Sciences, Suzhou Institute of Chinese Materia Medica, 2011 Collaborative Innovation Center of Hematology, University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, PR China. Electronic address: zhouqs@suda.edu.cn.
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, School of Biology and Basic Medical Sciences, Suzhou Institute of Chinese Materia Medica, 2011 Collaborative Innovation Center of Hematology, University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, PR China. Electronic address: hunancao@163.com.
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Cao
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D019684:Magnoliopsida / Q000737:chemistry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D016513:Mice, SCID; D010616:Phenanthrenes / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051742:Transcription Factor CHOP / Q000235:genetics; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: C497109:ATF4 protein, human; D000972:Antineoplastic Agents, Phytogenic; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D010616:Phenanthrenes; C573784:dehydroeffusol; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP
keywords: Apoptosis; Dehydroeffusol; ER stress; Gastric cancer; p38