title: Dasatinib inhibits TGFβ-induced myofibroblast differentiation through Src-SRF Pathway.
abstract: Persistent myofibroblast differentiation is a hallmark of fibrotic diseases. Myofibroblasts are characterized by de novo expression of alpha smooth muscle actin (αSMA) and excess fibronectin assembly. Recent studies provide conflicting reports on the effects of tyrosine kinase inhibitor dasatinib on myofibroblast differentiation and fibrosis. Also, it is not fully understood whether dasatinib modulates myofibroblast differentiation by targeting Src kinase. Herein, we investigated the effect of dasatinib on cSrc and transforming growth factor-β (TGFβ)-induced myofibroblast differentiation in vitro. Our results indicated that selective Src kinase inhibition using PP2 mimicked the effect of dasatinib in attenuating myofibroblast differentiation as evident by blunted αSMA expression and modest, but significant inhibition of fibronectin assembly in both NIH 3T3 and fibrotic human lung fibroblasts. Mechanistically, our data showed that dasatinib modulates αSMA synthesis through Src kinase-mediated modulation of serum response factor expression. Collectively, our results demonstrate that dasatinib modulates myofibroblast differentiation through Src-SRF pathway. Thus, dasatinib could potentially be a therapeutic option in fibrotic diseases.
authors.affiliation: Clinical 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.
authors.forename: Maha
authors.initials: M
authors.lastname: Abdalla
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States.
authors.forename: LeeAnn
authors.initials: L
authors.lastname: Thompson
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States.
authors.forename: Erin
authors.initials: E
authors.lastname: Gurley
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States.
authors.forename: Samantha
authors.initials: S
authors.lastname: Burke
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ujjin
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Newsome
authors.affiliation: Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States; Department of Medicine and Vascular Biology Center, Augusta, GA, United States; Cancer Center, Georgia Regents University, Augusta, GA, United States. Electronic address: sshenoy@gru.edu.
authors.forename: Payaningal R
authors.initials: PR
authors.lastname: Somanath
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D000069439:Dasatinib / Q000494:pharmacology*; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000473:pathology; D051379:Mice; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects*; D011658:Pulmonary Fibrosis / Q000473:pathology; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D005353:Fibronectins; D026362:Serum Response Factor; D016212:Transforming Growth Factor beta; D019061:src-Family Kinases; D000069439:Dasatinib
keywords: Dasatinib; Myofibroblast; Serum response factor; Src; TGFβ