5D) Based on numerous studies, TGF-β has been recognized as a pr

5D). Based on numerous studies, TGF-β has been recognized as a proapoptotic and profibrotic master cytokine in hepatocytes3, 9-11; therefore, we hypothesized that sorafenib may potentially exert both antiapoptotic and antifibrotic effects by disrupting TGF-β signaling. To test this hypothesis we first confirmed the protective effect selleck chemicals of sorafenib in blocking apoptosis in primary hepatocytes. As shown in Fig. 6A, caspase-3 activity was attenuated when cells were treated with sorafenib. Further experiments demonstrated

that exposure of primary hepatocytes to sorafenib eventually led to a significant decrease in the expression of proapoptotic genes, such as Bad, Bax, and Caspase 3 (Fig. 6B), indicating that this drug prevents hepatocytes from undergoing apoptosis. Because primary hepatocytes may also contribute to the production of ECM,8 we subsequently assessed the GSK126 manufacturer effects of sorafenib on collagen production in vitro. In response to external TGF-β1 stimulation, primary hepatocytes up-regulate the production of fibrotic matrix components, including procollagen type I (col I), procollagen type III (col III), and collagen IV α1. Interestingly, these changes were substantially attenuated after treatment with sorafenib (Fig. 6C), suggesting an antifibrotic role of

sorafenib in counteracting ECM accumulation. This effect was further supported by real-time qPCR analysis assessing gene expression profiles of sorafenib-treated hepatocytes, which revealed a profound decrease in the expression of Timp-3, a tissue inhibitor of metalloproteinases that is expressed only in hepatocytes.33 Likewise, the expression of the 上海皓元医药股份有限公司 potent profibrotic factors TGF-β1 and CCN2 (connective tissue growth factor) were reduced by ≈44% to 58% after sorafenib treatment (Fig.

6C). Taken together, these results clearly provide in vitro evidence that sorafenib exerts both antiapoptotic and antifibrotic effects against TGF-β signaling in mouse hepatocytes. In 2005, sorafenib became the first oral agent approved for the treatment of patients with advanced RCC. Previous reports have largely focused on the role of sorafenib in tumor progression and apoptosis through blocking multiple receptor tyrosine kinases.13-15, 34 In this study we uncovered a novel capacity of sorafenib to antagonize TGF-β signaling and, consequently, to counteract TGF-β1-induced concomitant EMT and apoptosis in mouse hepatocytes. We observed that sorafenib treatment significantly decreased Smad2/3 phosphorylation (Fig. 1C and Supporting Fig. S2) and the expression of TGF-β target genes, such as CCN2, ColIa1, and Smad7 (Figs. 1D, 5D, 6C), raising the possibility that sorafenib may directly or indirectly modify key proteins in the TGF-β signaling pathway.

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