title: Tangeretin enhances radiosensitivity and inhibits the radiation-induced epithelial-mesenchymal transition of gastric cancer cells.
abstract: Irradiation has been reported to increase radioresistance and epithelial-mesenchymal transition (EMT) in gastric cancer (GC) cells. The Notch pathway is critically implicated in cancer EMT and radioresistance. In the present study, we investigated the use of a Notch-1 inhibiting compound as a novel therapeutic candidate to regulate radiation-induced EMT in GC cells. According to previous screening, tangeretin, a polymethoxylated flavonoid from citrus fruits was selected as a Notch-1 inhibitor. Tangeretin enhanced the radiosensitivity of GC cells as demonstrated by MTT and colony formation assays. Tangeretin also attenuated radiation-induced EMT, invasion and migration in GC cells, accompanied by a decrease in Notch-1, Jagged1/2, Hey-1 and Hes-1 expressions. Tangeretin triggered the upregulation of miR-410, a tumor-suppressive microRNA. Furthermore, re-expression of miR-410 prevented radiation-induced EMT and cell invasion. An in vivo tumor xenograft model confirmed the antimetastasis effect of tangeretin as we observed in vitro. In nude mice, tumor size was considerably diminished by radiation plus tangeretin co-treatment. Tangeretin almost completely inhibited lung metastasis induced by irradiation. Tangeretin may be a novel antimetastatic agent for radiotherapy.
authors.affiliation: Department of General Surgery, PLA Jinan General Hospital, Jinan, Shandong 250031, P.R. China.
authors.forename: Xukui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, PLA Jinan General Hospital, Jinan, Shandong 250031, P.R. China.
authors.forename: Luming
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of General Surgery, PLA Jinan General Hospital, Jinan, Shandong 250031, P.R. China.
authors.forename: Yinggang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Medical School, Shangdong University, Jinan, Shandong 250012, P.R. China.
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Oncology, PLA Jinan General Hospital, Jinan, Shandong 250031, P.R. China.
authors.forename: Baocheng
authors.initials: B
authors.lastname: Wang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D047309:Flavones / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D000072100:Jagged-1 Protein; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D011836:Radiation Tolerance / Q000187:drug effects*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics; D000072099:Serrate-Jagged Proteins; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D047309:Flavones; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D035683:MicroRNAs; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; C485631:HEY1 protein, human; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C568527:MIRN410 microRNA, human; C497761:NOTCH1 protein, human; C078493:HES1 protein, human; C059006:tangeretin