title: Wnt5a attenuates the pathogenic effects of the Wnt/β-catenin pathway in human retinal pigment epithelial cells via down-regulating β-catenin and Snail.
abstract: Activation of the Wnt/β-catenin pathway plays a pathogenic role in age-related macular degeneration (AMD) and is thus a potential target for the development of therapeutics for this disease. Here, we demonstrated that Wnt5a antagonized β-catenin response transcription (CRT) induced with Wnt3a by promoting β-catenin phosphorylation at Ser33/Ser37/Thr41 and its subsequent degradation in human retinal pigment epithelial (RPE) cells. Wnt5a decreased the levels of vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB), which was up-regulated by Wnt3a. Furthermore, Wnt5a increased E-cadherin expression and decreased cell migration by down-regulating Snail expression, thereby abrogating the Wnt3a-induced epithelial-mesenchymal transition (EMT) in human RPE cells. Our findings suggest that Wnt5a suppresses the pathogenic effects of canonical Wnt signaling in human RPE cells by promoting β-catenin phosphorylation and degradation. Therefore, Wnt5a has significant therapeutic potential for the treatment of AMD.
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 02707, Korea.
authors.forename: Joo-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 02707, Korea.
authors.forename: Seoyoung
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Opthalmology, Konkuk University School of Medicine, Seoul 05066, Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Chung
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 02707, Korea.
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Oh
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D002478:Cells, Cultured; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D008268:Macular Degeneration / Q000188:drug therapy; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051153:Wnt Proteins / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D051176:beta Catenin