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. Epub 2014 Nov 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antibiotics, Antineoplastic / toxicity
  • Bleomycin / toxicity
  • Blotting, Western
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Depsipeptides / pharmacology*
  • Dishevelled Proteins
  • Fibroblasts / cytology
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Immunoenzyme Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • PDZ Domains / drug effects*
  • Phosphoproteins / antagonists & inhibitors*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / prevention & control*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Transforming Growth Factor beta1 / pharmacology
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antibiotics, Antineoplastic
  • Cadherins
  • Depsipeptides
  • Dishevelled Proteins
  • NSC 668036
  • Phosphoproteins
  • RNA, Messenger
  • Transforming Growth Factor beta1
  • beta Catenin
  • Bleomycin