title: A Small Dibromotyrosine Derivative Purified From Pseudoceratina Sp. Suppresses TGF-β Responsiveness by Inhibiting TGF-β Type I Receptor Serine/Threonine Kinase Activity.
abstract: For clinical application, there is a great need for small-molecule inhibitors (SMIs) that could control pathogenic effects of transforming growth factor (TGF-β) and/or modulate effects of TGF-β in normal responses. Selective SMIs of the TGF-β signaling pathway developed for therapeutics will also be powerful tools in experimentally dissecting this complex pathway, especially its cross-talk with other signaling pathways. In this study, we characterized (1'R,5'S,6'S)-2-(3',5'-dibromo-1',6'-dihydroxy-4'-oxocyclohex-2'-enyl) acetonitrile (DT), a member of a new class of small-molecule inhibitors related to bromotyrosine derivate from Pseudoceratina sp., which inhibits the TGF-β type I receptor serine/threonine kinase known as activin receptor-like kinase (ALK) 5. The inhibitory effects of DT on TGF-β-induced Smad signaling and epithelial-to-mesenchymal transition (EMT) were investigated in epithelial cells using in vitro kinase assay, luciferase reporter assays, immunoblotting, confocal microscopy, and wound healing assays. The novel ALK5 inhibitor, DT, inhibited the TGF-β-stimulated transcriptional activations of 3TP-Lux. In addition, DT decreased phosphorylated Smad2/3 levels and the nuclear translocation of Smad2/3 increased by TGF-β. In addition, DT inhibited TGF-β-induced EMT and wound healing of A549 cells. Our results suggest that DT is a potential therapeutic agent for fibrotic disease and cancer treatment. J. Cell. Biochem. 117: 2800-2814, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biological Science, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, ROC. chunlinchen@mail.nsysu.edu.tw.|Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, 80424, Taiwan, ROC. chunlinchen@mail.nsysu.edu.tw.
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Biological Science, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, ROC.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Kao
authors.affiliation: Department of Biological Science, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, ROC.
authors.forename: Pei-Hua
authors.initials: PH
authors.lastname: Yang
authors.affiliation: Graduate Institute of Marine Biology, National Dong Hwa University, Hualien 97401, Taiwan, ROC.|National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan, ROC.
authors.forename: Ping-Jyun
authors.initials: PJ
authors.lastname: Sung
authors.affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, ROC.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Wen
authors.affiliation: Department of Pharmacy and Graduate Institute of Pharmaceutical Technology, Tajen University, Pingtung 907, Taiwan, ROC.
authors.forename: Jih-Jung
authors.initials: JJ
authors.lastname: Chen
authors.affiliation: Department of Biological Science, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, ROC.
authors.forename: Yaw-Bin
authors.initials: YB
authors.lastname: Huang
authors.affiliation: Department of Biological Science, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, ROC.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Chen
mesh_terms: D000097:Acetonitriles / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003512:Cyclohexanones / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011161:Porifera / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C000621984:2-(3',5'-dibromo-1',6'-dihydroxy-4'-oxocyclohex-2'-enyl)acetonitrile; D000097:Acetonitriles; D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C475724:bromotyrosine; D014443:Tyrosine; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human
keywords: BROMOTYROSINE DERIVATIVE; MARINE NATURAL PRODUCT; SMALL MOLECULE INHIBITORS; TGF-β