Abdalla Maha, Thompson LeeAnn, Gurley Erin, Burke Samantha, Ujjin Jessica, Newsome Robert, Somanath Payaningal R
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.
Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and Charlie Norwood VA Medical Center, Augusta, GA 30912, United States.
Eur J Pharmacol. 2015 Dec 15;769:134-42. doi: 10.1016/j.ejphar.2015.11.008. Epub 2015 Nov 6.
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.
持续性肌成纤维细胞分化是纤维化疾病的一个标志。肌成纤维细胞的特征是α平滑肌肌动蛋白（αSMA）的从头表达和过量的纤连蛋白组装。最近的研究关于酪氨酸激酶抑制剂达沙替尼对肌成纤维细胞分化和纤维化的影响给出了相互矛盾的报告。此外，达沙替尼是否通过靶向Src激酶来调节肌成纤维细胞分化尚不完全清楚。在此，我们研究了达沙替尼对体外cSrc和转化生长因子-β（TGFβ）诱导的肌成纤维细胞分化的影响。我们的结果表明，使用PP2选择性抑制Src激酶模拟了达沙替尼在减弱肌成纤维细胞分化方面的作用，这在NIH 3T3细胞和纤维化的人肺成纤维细胞中均表现为αSMA表达减弱以及纤连蛋白组装受到适度但显著的抑制。从机制上讲，我们的数据表明达沙替尼通过Src激酶介导的血清反应因子表达调节来调节αSMA的合成。总体而言，我们的结果证明达沙替尼通过Src-SRF途径调节肌成纤维细胞分化。因此，达沙替尼可能是纤维化疾病的一种潜在治疗选择。
