title: Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy.
abstract: Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy.
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Shilong
authors.initials: S
authors.lastname: Fu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Huaidong
authors.initials: H
authors.lastname: Liao
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Zihe
authors.initials: Z
authors.lastname: Huo
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Gaochuan
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Aidi
authors.initials: A
authors.lastname: Gao
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu 215123, China; The First Affiliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: zhouqs@suda.edu.cn.
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Zhou
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004187:Disaccharides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D047309:Flavones / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000972:Antineoplastic Agents, Phytogenic; C497249:DDIT3 protein, human; D004187:Disaccharides; D004365:Drugs, Chinese Herbal; D000091342:Endoplasmic Reticulum Chaperone BiP; D047309:Flavones; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; C000604116:oroxin B; D051742:Transcription Factor CHOP; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human
keywords: Apoptosis; Cancer therapy; DDIT3; ER stress; GRP78; Lymphoma; Oroxin B