|Title:||Inhibition of the Wnt/beta-catenin signaling pathway improves the anti-tumor effects of sorafenib against hepatocellular carcinoma||Authors:||Lin, Hsiao-Hui
|Keywords:||Wnt/beta-catenin;Sorafenib;ICG-001;Hepatocellular carcinoma||Issue Date:||2016||Journal Volume:||381||Journal Issue:||1||Start page/Pages:||58-66||Source:||Cancer Lett.||Abstract:||
Sorafenib, a multikinase inhibitor, is currently the only approved drug for advanced hepatocellular carcinoma (HCC). The current study tested the hypothesis whether inhibition of the Wnt/beta-catenin signaling pathway could improve the anti-tumor effects of sorafenib in HCC. ICG-001, a small molecule which blocks the interaction of beta-catenin with its transcriptional coactivator CBP, dose-dependently enhanced the growth suppressive and apoptosis-induction effects of sorafenib in multiple HCC cell lines. Downregulation of beta-catenin by RNA interference increased sorafenib sensitivity, whereas overexpression of beta-catenin reduced sorafenib sensitivity in Huh7 cells. The sorafenib-sensitization effect of short hairpin RNA (shRNA)-mediated beta-catenin downregulation in Huh7 cells was attenuated by beta-catenin overexpression. Mechanistically, sorafenib combined with ICG-001 or shRNA-mediated beta-catenin downregulation augmented the induction of apoptosis, and resulted in a significant downregulation of Mcl-1 in HCC cells. In Huh7 cell mouse xenograft model, the combination of ICG-001 and sorafenib showed a more significant growth-retarding effect than single agent treatment of sorafenib or ICG-001. Our data indicate that inhibition of the Wnt/beta-catenin signaling pathway improves the antitumor effects of sorafenib against HCC in vitro and in vivo. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
|Appears in Collections:||腫瘤醫學研究所|
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