Liver X Receptor Agonism Sensitizes a Subset of Hepatocellular Carcinoma to Sorafenib by Dual-Inhibiting MET and EGFR
Liver X Receptor Agonism Sensitizes a Subset of Hepatocellular Carcinoma to Sorafenib by Dual-Inhibiting MET and EGFR
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DOI：
10.1016/j.neo.2019.08.002
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发表时间：
2020-01-01
期刊：
影响因子：
4.8
通讯作者：
Chen, Jinhong
中科院分区：
文献类型：
--
作者：
Shao, Weiqing;Zhu, Wenwei;Chen, Jinhong
索拉非尼是首个被批准用于晚期肝细胞癌（HCC）的全身治疗药物，也是临床的一线选择。受体酪氨酸激酶（RTKs）的持续激活与索拉非尼治疗HCC的低疗效相关。据报道，肝脏X受体（LXR）的激活可以抑制一些rtk。在本研究中，我们发现LXR激动剂增强了索拉非尼在高LXR- β / α基因表达比的HCC细胞亚群中的抗肿瘤活性。机械地，LXR的激活抑制索拉非尼依赖性募集MET和表皮生长因子受体（EGFR）在脂筏通过胆固醇外排。我们的研究结果表明LXR激动剂可以作为潜在的增敏剂增强索拉非尼的抗肿瘤作用。
Sorafenib is the first approved systemic therapy for advanced hepatocellular carcinoma (HCC) and is the first-line choice in dinic. Sustained activation of receptor tyrosine kinases (RTKs) is associated with low efficacy of sorafenib in HCC. Activation of liver X receptor (LXR) has been reported to inhibit some RTKs. In this study, we found that the LXR agonist enhanced the anti-tumor activity of sorafenib in a subset of HCC cells with high LXR-beta/alpha gene expression ratio. Mechanically, the activation of LXR suppressed sorafenib dependent recruitment of MET and epidermal growth factor receptor (EGFR) in lipid rafts through cholesterol efflux. Our findings imply that LXR agonist can serve as a potential sensitizer to enhance the anti-tumor effect of sorafenib.