LY3214996 relieves acquired resistance to sorafenib in hepatocellular carcinoma cells.
LY3214996 relieves acquired resistance to sorafenib in hepatocellular carcinoma cells.
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LY3214996缓解肝细胞癌细胞对索拉非尼的获得性耐药
DOI：
10.7150/ijms.51256
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发表时间：
2021
影响因子：
3.6
通讯作者：
Tang X
中科院分区：
文献类型：
--
作者：
Ma Y;Xu R;Liu X;Zhang Y;Song L;Cai S;Zhou S;Xie Y;Li A;Cao W;Tang X
背景资料：索拉非尼是一种快速加速纤维肉瘤的口服多激酶抑制剂;血管内皮生长因子受体-2/3、血小板衍生生长因子受体、c-Kit和Flt-3信号传导，被批准用于治疗晚期肝细胞癌（HCC）。然而，索拉非尼的益处通常由于通过索拉非尼抗性HCC细胞中ERK信号转导的再激活而获得的抗性而减少。在这项工作中，我们研究了是否添加LY3214996，选择性ERK 1/2抑制剂，索拉非尼将增加索拉非尼对肝癌细胞的抗肿瘤效果。方法：Huh 7细胞系用作索拉非尼、LY3214996及其组合处理的细胞模型。Western blot检测Ras/Raf/MAPK和PI3K/Akt通路中关键激酶的磷酸化、细胞周期蛋白表达和凋亡迁移。MTT法和集落形成实验检测细胞增殖情况。伤口愈合测定用于评估细胞迁移。流式细胞仪检测细胞周期和凋亡。结果如下：LY3214996降低了Ras/Raf/MAPK和PI3K/Akt通路的磷酸化，包括索拉非尼激活的p-c-Raf、p-P90 RSK、p-S6 K和p-eIF4 EBP 1，尽管p-ERK 1/2水平升高。LY3214996增加了索拉非尼对Huh7R细胞的抗增殖、抗迁移、细胞周期进展和促凋亡作用。结论：ERK 1/2的重新激活可能是肝癌对索拉非尼获得性耐药的分子机制。LY3214996联合索拉非尼可增强索拉非尼的抗肝癌作用。这些发现为LY3214996联合索拉非尼作为索拉非尼耐药的晚期肝癌二线治疗试验提供了理论基础。
Background: Sorafenib, an oral multi-kinase inhibitor of rapidly accelerated fibrosarcoma; vascular endothelial growth factor receptor-2/3, platelet-derived growth factor receptor, c-Kit, and Flt-3 signaling, is approved for treatment of advanced hepatocellular carcinoma (HCC). However, the benefit of sorafenib is often diminished because of acquired resistance through the reactivation of ERK signaling in sorafenib-resistant HCC cells. In this work, we investigated whether adding LY3214996, a selective ERK1/2 inhibitor, to sorafenib would increase the anti-tumor effectiveness of sorafenib to HCC cells. Methods: The Huh7 cell line was used as a cell model for treatment with sorafenib, LY3214996, and their combination. Phosphorylation of the key kinases in the Ras/Raf/MAPK and PI3K/Akt pathways, protein expression of the cell cycle, and apoptosis migration were assessed with western blot. MTT and colony-formation assays were used to evaluate cell proliferation. Wound-healing assay was used to assess cell migration. Cell cycle and apoptosis analyses were conducted with flow cytometry. Results: LY3214996 decreased phosphorylation of the Ras/Raf/MAPK and PI3K/Akt pathways, including p-c-Raf, p-P90RSK, p-S6K and p-eIF4EBP1 activated by sorafenib, despite increased p-ERK1/2 levels. LY3214996 increased the anti-proliferation, anti-migration, cell-cycle progression, and pro-apoptotic effects of sorafenib on Huh7R cells. Conclusions: Reactivation of ERK1/2 appears to be a molecular mechanism of acquired resistance of HCC to sorafenib. LY3214996 combined with sorafenib enhanced the anti-tumor effects of sorafenib in HCC. These findings form a theoretical basis for trial of LY3214996 combined with sorafenib as second-line treatment of sorafenib-resistant in advanced HCC.
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