Dasatinib inhibits TGFβ-induced myofibroblast differentiation through Src-SRF Pathway.
Dasatinib inhibits TGFβ-induced myofibroblast differentiation through Src-SRF Pathway.
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DOI：
10.1016/j.ejphar.2015.11.008
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发表时间：
2015-12-15
影响因子：
5
通讯作者：
Somanath PR
中科院分区：
文献类型：
--
作者：
Abdalla M;Thompson L;Gurley E;Burke S;Ujjin J;Newsome R;Somanath PR
持续的肌成纤维细胞分化是纤维化疾病的标志。肌成纤维细胞的特征是从头表达α平滑肌肌动蛋白（αSMA）和过量的纤连蛋白组装。最近的研究提供了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影响的相互矛盾的报告。此外，尚不完全清楚达沙替尼是否通过靶向 Src 激酶来调节肌成纤维细胞分化。在此，我们研究了达沙替尼对 cSrc 和转化生长因子-β (TGFβ) 体外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 Src 激酶抑制模拟了达沙替尼在减弱肌成纤维细胞分化方面的作用，这一点可以通过 αSMA 表达减弱以及对 NIH 3T3 和纤维化人肺成纤维细胞中纤连蛋白组装的适度但显着的抑制来证明。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 合成。总的来说，我们的结果表明达沙替尼通过 Src-SRF 途径调节肌成纤维细胞分化。因此，达沙替尼可能成为纤维化疾病的一种治疗选择。
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.