title: Oroxin A inhibits breast cancer cell growth by inducing robust endoplasmic reticulum stress and senescence.
abstract: Breast cancer is a major cause of cancer death among women. Although various anticancer drugs have been used in clinics, drugs that are effective against advanced and metastatic breast cancer are still lacking and in great demand. In this study, we found that oroxin A, an active component isolated from the herb Oroxylum indicum (L.) Kurz, effectively inhibited the growth of human breast cancer cells MDA-MB-231 and MCF7 by inducing endoplasmic reticulum (ER) stress-mediated senescence. Oroxin A caused breast cancer cell cycle arrest at the G2/M stage, and reorganization of microtubules and actin cytoskeleton accompanied by a decrease in cellular mitosis. ER-specific probe ER-Tracker Red and confocal microscope imaging showed that ER-Tracker Red-positive cells increased in an oroxin A dosage-dependent manner. In addition, oroxin A increased cell population with high β-Gal activity and SAHF-positive staining; these data suggest that oroxin A induces breast cancer cell ER stress and senescence. Mechanistic studies showed that oroxin A led to a significant increase in intracellular reactive oxygen species levels, promoted expression of ER stress markers ATF4 and GRP78, and increased the phosphorylation of a key stress-response signaling protein p38, resulting in an ER stress-mediated senescence. Taken together, our data indicate that oroxin A exerts its antibreast cancer effects by inducing ER stress-mediated senescence, activating the key stress p38 signaling pathway, and increasing key ER stress genes ATF4 and GRP78 expression levels.
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, 2011 Collaborative Innovation Center of Hematology, Key Laboratory of Thrombosis and Hemostasis, The First Affiliated Hospital of Soochow University, Ministry of Health, Soochow University, Suzhou, Jiangsu, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.forename: Longsheng
authors.initials: L
authors.lastname: Du
authors.forename: Meimei
authors.initials: M
authors.lastname: Bao
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Haixin
authors.initials: H
authors.lastname: Qian
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Zhou
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Cao
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D047309:Flavones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D005960:Glucosides / Q000494:pharmacology*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D047309:Flavones; D005419:Flavonoids; D005960:Glucosides; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000608364:oroxin A; D051701:Activating Transcription Factor 4; D001616:beta-Galactosidase