title: BIX02189 inhibits TGF-β1-induced lung cancer cell metastasis by directly targeting TGF-β type I receptor.
abstract: Transforming growth factor-β1 (TGF-β1) promotes tumor metastasis by inducing an epithelial-to-mesenchymal transition (EMT) in cancer cells. In this study, we investigated the effects of BIX02189 and XMD8-92, pharmacologic inhibitors of the MEK5 [mitogen-activated protein kinase/extracellular-signal-regulated kinase (ERK)5] signaling pathway, on the EMT and migration of cancer cells induced by TGF-β1. In human A549 lung cancer cells, TGF-β1-induced EMT, cell motility, and expression of matrix metalloproteinase-2 were completely inhibited by BIX02189, but not by XMD8-92 or small interference RNAs specific to MEK5 and ERK5. Interestingly, BIX02189 strongly blocked the activation of TGF-β1 signaling components, and this inhibitory effect was not reproduced by MEK5 inhibition. Molecular docking simulation and kinase assays revealed that BIX02189 binds directly to the ATP-binding site of the TGF-β receptor type I (TβRI) and suppresses its kinase activity. Finally, the anti-metastatic effect of BIX02189 was validated in a TβRI-derived A549 xenograft mouse model. Collectively, these findings newly characterize BIX02189 as a potent inhibitor of TβRI that can block the tumor metastatic activity of TGF-β1.
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Seong Ji
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Yu Sun
authors.initials: YS
authors.lastname: Choi
authors.affiliation: Department of Anatomic Pathology, Kangwon National University Hospital, School of Medicine, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Seungkoo
authors.initials: S
authors.lastname: Lee
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea.
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea.
authors.forename: Suntaek
authors.initials: S
authors.lastname: Hong
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Sanghwa
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea. Electronic address: bckim@kangwon.ac.kr.
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Kim
mesh_terms: D000072283:A549 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D002465:Cell Movement / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048671:MAP Kinase Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C533207:BIX 02189; D007211:Indoles; D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; C481581:MAPK7 protein, human; D048054:Mitogen-Activated Protein Kinase 7; D000077293:Receptor, Transforming Growth Factor-beta Type I; D048671:MAP Kinase Kinase 5; C482563:MAP2K5 protein, human
keywords: BIX02189; EMT; Lung cancer; TGF-β1; TβRI