Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process

Wang, Cong; Dai, Jinghong; Sun, Zhaorui; Shi, Chaowen; Cao, Honghui; others, and

doi:10.1016/J.YEXCR.2014.10.023

Title: Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process

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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. - Highlights: • NSC668036 inhibited the proliferation and migration of NIH/3T3 fibroblasts. • NSC668036 suppressed the Wnt/β-catenin signaling pathway. • TGF-β-induced stimulation of profibrotic responses were inhibited by NSC668036. • NSC668036 can inhibit the development of bleomycin-induced pulmonary fibrosis.

Authors:

Wang, Cong ^[1]; Dai, Jinghong ^[2]; Sun, Zhaorui ^[1]; Shi, Chaowen ^[1]; Cao, Honghui ^[1]; others, and

Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China)
Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University (China)

Publication Date:: Sun Feb 01 00:00:00 EST 2015

OSTI Identifier:: 22462256

Resource Type:: Journal Article

Journal Name:: Experimental Cell Research

Additional Journal Information:: Journal Volume: 331; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0014-4827

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; ACTIN; BLEOMYCIN; BUILDUP; COLLAGEN; DISEASES; FIBROBLASTS; FIBROSIS; GENES; GROWTH FACTORS; IN VITRO; IN VIVO; INHIBITION; LUNGS; MIGRATION; MUSCLES; PROLIFERATION; SIGNALS; STIMULATION; TRANSCRIPTION

Citation Formats


                    Wang, Cong, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, Dai, Jinghong, Sun, Zhaorui, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, Department of Emergency, Jinling Hospital, Medical School, Nanjing University, Nanjing, Jiangsu 210093, Shi, Chaowen, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, Cao, Honghui, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, and others, and. Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process.  United States: N. p., 2015. 
        Web.  doi:10.1016/J.YEXCR.2014.10.023.

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                    Wang, Cong, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, Dai, Jinghong, Sun, Zhaorui, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, Department of Emergency, Jinling Hospital, Medical School, Nanjing University, Nanjing, Jiangsu 210093, Shi, Chaowen, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, Cao, Honghui, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, & others, and. Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process.  United States.  https://doi.org/10.1016/J.YEXCR.2014.10.023

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                    Wang, Cong, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, Dai, Jinghong, Sun, Zhaorui, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, Department of Emergency, Jinling Hospital, Medical School, Nanjing University, Nanjing, Jiangsu 210093, Shi, Chaowen, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, Cao, Honghui, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, and others, and. 2015.  
        "Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process".  United States.  https://doi.org/10.1016/J.YEXCR.2014.10.023.

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@article{osti_22462256,

  title        = {Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process},

  author       = {Wang, Cong and Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 and State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 and Dai, Jinghong and Sun, Zhaorui and Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 and State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 and Department of Emergency, Jinling Hospital, Medical School, Nanjing University, Nanjing, Jiangsu 210093 and Shi, Chaowen and Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 and State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 and Cao, Honghui and Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 and State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 and others, and},

  abstractNote = {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. - Highlights: • NSC668036 inhibited the proliferation and migration of NIH/3T3 fibroblasts. • NSC668036 suppressed the Wnt/β-catenin signaling pathway. • TGF-β-induced stimulation of profibrotic responses were inhibited by NSC668036. • NSC668036 can inhibit the development of bleomycin-induced pulmonary fibrosis.},

  doi          = {10.1016/J.YEXCR.2014.10.023},

  url          = {https://www.osti.gov/biblio/22462256},
  journal      = {Experimental Cell Research},

  issn         = {0014-4827},

  number       = 1,

  volume       = 331,

  place        = {United States},

  year         = {Sun Feb 01 00:00:00 EST 2015},

  month        = {Sun Feb 01 00:00:00 EST 2015}

}

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