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Dasatinib inhibits TGFβ-induced myofibroblast differentiation through Src-SRF Pathway

Maha Abdalla1, LeeAnn Thompson2, Erin Gurley2

  • 1Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States; Department of Pharmaceutical Sciences, South College School of Pharmacy, Knoxville, TN, United States.

European Journal of Pharmacology
|November 10, 2015
PubMed

Insights

The tyrosine kinase inhibitor dasatinib reduces myofibroblast differentiation, a key factor in fibrosis. This effect is mediated through the Src-SRF pathway, suggesting dasatinib as a potential therapy for fibrotic diseases.

Area of Science:

  • Cell Biology
  • Pharmacology
  • Fibrosis Research

Background:

  • Persistent myofibroblast differentiation drives fibrotic diseases.
  • Myofibroblasts express alpha smooth muscle actin (αSMA) and assemble fibronectin.
  • The role of dasatinib in myofibroblast differentiation and fibrosis remains unclear.

Purpose of the Study:

  • To investigate dasatinib's effect on transforming growth factor-β (TGFβ)-induced myofibroblast differentiation.
  • To determine if dasatinib targets Src kinase in myofibroblast differentiation.
  • To elucidate the mechanism by which dasatinib modulates myofibroblast differentiation.

Main Methods:

  • In vitro study using NIH 3T3 and human lung fibroblasts.
  • Treatment with dasatinib and PP2 (a selective Src kinase inhibitor).
  • Assessment of αSMA expression and fibronectin assembly.

Main Results:

  • Dasatinib attenuated myofibroblast differentiation, reducing αSMA expression and fibronectin assembly.
  • Selective Src kinase inhibition with PP2 mimicked dasatinib's effects.
  • Dasatinib modulates αSMA synthesis via Src kinase-mediated regulation of serum response factor (SRF).

Conclusions:

  • Dasatinib modulates myofibroblast differentiation through the Src-SRF pathway.
  • This mechanism highlights dasatinib's potential as a therapeutic agent for fibrotic diseases.
Keywords:
DasatinibMyofibroblastSerum response factorSrcTGFβ

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