Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process
Copyright policy )Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process
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.
- Nanjing University China (People's Republic of)
- Nanjing University China (People's Republic of)
- Nanjing General Hospital of Nanjing Military Command China (People's Republic of)
- State Key Laboratory of Digital Medical Engineering China (People's Republic of)
- Southeast University China (People's Republic of)
Male, Antibiotics, Antineoplastic, Blotting, Western, Dishevelled Proteins, Fluorescent Antibody Technique, PDZ Domains, Fibroblasts, Cadherins, Flow Cytometry, Phosphoproteins, Immunoenzyme Techniques, Mice, Inbred C57BL, Bleomycin, Mice, Depsipeptides, NIH 3T3 Cells, Animals, Cells, Cultured, Adaptor Proteins, Signal Transducing, Cell Proliferation
Male, Antibiotics, Antineoplastic, Blotting, Western, Dishevelled Proteins, Fluorescent Antibody Technique, PDZ Domains, Fibroblasts, Cadherins, Flow Cytometry, Phosphoproteins, Immunoenzyme Techniques, Mice, Inbred C57BL, Bleomycin, Mice, Depsipeptides, NIH 3T3 Cells, Animals, Cells, Cultured, Adaptor Proteins, Signal Transducing, Cell Proliferation
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