Abstract
In this study, we determined the effects of transforming growth factor-beta (TGF-β) and Wnt/β-catenin signaling on myofibroblast differentiation of NIH/3T3 fibroblasts in vitro and evaluated the therapeutic efficacy of NSC668036 in bleomycin-induced pulmonary fibrosis murine model. In vitro study, NSC668036, a small organic inhibitor of the PDZ domain in Dvl, suppressed β-catenin-driven gene transcription and abolished TGF-β1-induced migration, expression of collagen I and α-smooth muscle actin (α-SMA) in fibroblasts. In vivo study, we found that NSC668036 significantly suppressed accumulation of collagen I, α-SMA, and TGF-β1 but increased the expression of CK19, Occludin and E-cadherin that can inhibit pulmonary fibrogenesis. Because fibrotic lung exhibit aberrant activation of Wnt/β-catenin signaling, these data collectively suggest that inhibition of Wnt/β-catenin signaling at the Dvl level may be an effective approach to the treatment of fibrotic lung diseases.
Keywords:
Fibroblast; Idiopathic pulmonary fibrosis; Myofibroblast; NSC668036; Wnt signaling pathway.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antibiotics, Antineoplastic / toxicity
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Bleomycin / toxicity
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Blotting, Western
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Cadherins / genetics
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Cadherins / metabolism
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Cell Proliferation
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Cells, Cultured
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Depsipeptides / pharmacology*
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Dishevelled Proteins
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Fibroblasts / cytology
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Fibroblasts / drug effects*
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Fibroblasts / metabolism
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Flow Cytometry
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Fluorescent Antibody Technique
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Immunoenzyme Techniques
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Male
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Mice
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Mice, Inbred C57BL
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NIH 3T3 Cells
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PDZ Domains / drug effects*
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Phosphoproteins / antagonists & inhibitors*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Pulmonary Fibrosis / chemically induced
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Pulmonary Fibrosis / metabolism
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Pulmonary Fibrosis / prevention & control*
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects*
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Transforming Growth Factor beta1 / pharmacology
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Antibiotics, Antineoplastic
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Cadherins
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Depsipeptides
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Dishevelled Proteins
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NSC 668036
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Phosphoproteins
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RNA, Messenger
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Transforming Growth Factor beta1
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beta Catenin
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Bleomycin