Liu Huayuan, Zhao Lei, Wang Mengya, Yang Kexin, Jin Zhipeng, Zhao Chengjian, Shi Guangjun
Department of Hepatobiliary Surgery, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China.
Department of Infection Management, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, China.
Front Oncol. 2022 Mar 22;12:852095. doi: 10.3389/fonc.2022.852095. eCollection 2022.
In this study, we aimed to reveal the resistance mechanism of hepatocellular carcinoma (HCC) cells to sorafenib by exploring the effect of FNDC5 on sorafenib-induced ferroptosis in HCC cells. We compared the expression level of FNDC5 between sorafenib-resistant and sorafenib-sensitive HCC cell lines and the level of ferroptosis between the groups after treatment with sorafenib. We knocked down FNDC5 in drug-resistant cell lines and overexpressed it in sorafenib-sensitive HCC cell lines to further demonstrate the role of FNDC5 in sorafenib-induced ferroptosis. Using PI3K inhibitors, we revealed the specific mechanism by which FNDC5 functions. In addition, we verified our findings obtained in experiments using a subcutaneous tumorigenic nude mouse model. The findings revealed that FNDC5 inhibits sorafenib-induced ferroptosis in HCC cells. In addition, FNDC5 activated the PI3K/Akt pathway, which in turn promoted the nuclear translocation of Nrf2 and increased the intracellular antioxidant response, thereby conferring resistance to ferroptosis. Our study provides novel insights for improving the efficacy of sorafenib.
在本研究中，我们旨在通过探索纤连蛋白结构域包含蛋白5（FNDC5）对索拉非尼诱导的肝癌（HCC）细胞铁死亡的影响，揭示HCC细胞对索拉非尼的耐药机制。我们比较了索拉非尼耐药和索拉非尼敏感的HCC细胞系之间FNDC5的表达水平，以及用索拉非尼处理后各组之间的铁死亡水平。我们在耐药细胞系中敲低FNDC5，并在索拉非尼敏感的HCC细胞系中过表达它，以进一步证明FNDC5在索拉非尼诱导的铁死亡中的作用。使用磷脂酰肌醇-3-激酶（PI3K）抑制剂，我们揭示了FNDC5发挥作用的具体机制。此外，我们使用皮下致瘤裸鼠模型验证了在实验中获得的结果。研究结果表明，FNDC5抑制索拉非尼诱导的HCC细胞铁死亡。此外，FNDC5激活PI3K/蛋白激酶B（Akt）通路，进而促进核因子E2相关因子2（Nrf2）的核转位并增加细胞内抗氧化反应，从而赋予对铁死亡的抗性。我们的研究为提高索拉非尼的疗效提供了新的见解。
