Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process

  • Exp Cell Res. 2015 Feb 1;331(1):115-122. doi: 10.1016/j.yexcr.2014.10.023.
Cong Wang  1 ,  Jinghong Dai  2 ,  Zhaorui Sun  3 ,  Chaowen Shi  4 ,  Honghui Cao  5 ,  Xiang Chen  6 ,  Shen Gu  7 ,  Zutong Li  8 ,  Weiping Qian  9 ,  Xiaodong Han  10
Affiliations
  • 1. Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, China. Electronic address: [email protected].
  • 2. Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University, China. Electronic address: [email protected].
  • 3. Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, China; Department of Emergency, Jinling Hospital, Medical School, Nanjing University, Nanjing, Jiangsu 210093, China. Electronic address: [email protected].
  • 4. Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, China. Electronic address: [email protected].
  • 5. Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, China. Electronic address: [email protected].
  • 6. Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, China. Electronic address: [email protected].
  • 7. Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, China. Electronic address: [email protected].
  • 8. Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, China. Electronic address: [email protected].
  • 9. State Key Laboratory of Bioelectronics, Southeast University, Nanjing, China. Electronic address: [email protected].
  • 10. Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093, China. Electronic address: [email protected].
PMID: 25445788 DOI: 10.1016/j.yexcr.2014.10.023
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.
Products