Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, China.
CAS Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China.
Carcinogenesis. 2021 May 28;42(5):753-761. doi: 10.1093/carcin/bgab019.
Sorafenib is commonly used to treat advanced human hepatocellular carcinoma (HCC). However, clinical efficacy has been limited by drug resistance. In this study, we used label-free quantitative proteomic analysis to systematically investigate the underlying mechanisms of sorafenib resistance in HCC cells. A total of 1709 proteins were confidently quantified. Among them, 89 were differentially expressed and highly enriched in the processes of cell-cell adhesion, negative regulation of apoptosis, response to drug and metabolic processes involving in sorafenib resistance. Notably, folate receptor α (FOLR1) was found to be significantly upregulated in resistant HCC cells. In addition, in vitro studies showed that overexpression of FOLR1 decreased the sensitivity of HCC cells to sorafenib, whereas siRNA-directed knockdown of FOLR1 increased the sensitivity of HCC cells to sorafenib. Immunoprecipitation-mass spectrometry analysis suggested a strong link between FOLR1 and autophagy-related proteins. Further biological experiments found that FOLR1-related sorafenib resistance was accompanied by the activation of autophagy, whereas inhibition of autophagy significantly reduced FOLR1-induced cell resistance. These results suggest the driving role of FOLR1 in HCC resistance to sorafenib, which may be exerted through FOLR1-induced autophagy. Therefore, this study may provide new insights into understanding the mechanism of sorafenib resistance.
索拉非尼通常用于治疗晚期人肝癌（HCC）。然而，临床疗效受到耐药性的限制。在这项研究中，我们使用无标记定量蛋白质组学分析系统地研究了 HCC 细胞中索拉非尼耐药的潜在机制。共定量了 1709 种蛋白质。其中，89 种在细胞间黏附、细胞凋亡的负调控、对药物的反应以及涉及索拉非尼耐药的代谢过程中差异表达且高度富集。值得注意的是，在耐药 HCC 细胞中发现叶酸受体α（FOLR1）显著上调。此外，体外研究表明，FOLR1 的过表达降低了 HCC 细胞对索拉非尼的敏感性，而 FOLR1 的 siRNA 介导的敲低增加了 HCC 细胞对索拉非尼的敏感性。免疫沉淀-质谱分析表明 FOLR1 与自噬相关蛋白之间存在很强的联系。进一步的生物学实验发现，FOLR1 相关的索拉非尼耐药伴随着自噬的激活，而自噬的抑制显著降低了 FOLR1 诱导的细胞耐药性。这些结果表明 FOLR1 在 HCC 对索拉非尼耐药中起驱动作用，可能是通过 FOLR1 诱导的自噬来发挥作用。因此，本研究可能为理解索拉非尼耐药机制提供新的见解。
