The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China.
College of Life Science and Technology, Jinan University, Guangzhou, China.
Eur J Pharmacol. 2022 Sep 15;931:175186. doi: 10.1016/j.ejphar.2022.175186. Epub 2022 Aug 14.
Tumor chemoresistance is often a major cause for the failure of chemotherapy. The resistance of hepatocellular carcinoma (HCC) cells to sorafenib significantly limits its therapeutic effect in HCC patients. For the first time, we found that FXYD domain-containing ion transport regulator 5 (FXYD5) is highly expressed in sorafenib-resistant HCC cells. In addition, the protein expression level of FXYD5 was markedly higher in HCC tissues than in paracancerous tissues. Remarkably, downregulation of FXYD5 expression in Huh7/sora cells reversed their resistance to sorafenib. Moreover, overexpression of FXYD5 reduced the sensitivity of HCC cells to sorafenib, while the downregulation of its expression in HCC cells had the opposite effect. We also found abnormal activation of the Akt/mTOR signaling pathway in Huh7/sora cells. Furthermore, MK2206, an Akt inhibitor, was found to significantly increase the sensitivity of HCC cells to sorafenib. More importantly, the expression level of p-Akt was positively correlated with the expression of FXYD5 in HCC tissues. Therefore, mechanistically, FXYD5 enhances the resistance of HCC cells to sorafenib by activating the Akt/mTOR signaling pathway. In conclusion, this study showed that the activation of the FXYD5/Akt/mTOR signaling axis plays key role in the resistance of HCC cells to sorafenib, and FXYD5 may represent a new potential target for HCC therapy.
肿瘤的化疗耐药性常常是化疗失败的主要原因。肝癌（HCC）细胞对索拉非尼的耐药性显著限制了其在 HCC 患者中的治疗效果。我们首次发现，FXYD 结构域包含的离子转运调节剂 5（FXYD5）在索拉非尼耐药的 HCC 细胞中高表达。此外，FXYD5 的蛋白表达水平在 HCC 组织中明显高于癌旁组织。值得注意的是，下调 Huh7/sora 细胞中 FXYD5 的表达可逆转其对索拉非尼的耐药性。此外，过表达 FXYD5 降低了 HCC 细胞对索拉非尼的敏感性，而下调其在 HCC 细胞中的表达则产生相反的效果。我们还发现 Huh7/sora 细胞中 Akt/mTOR 信号通路异常激活。此外，发现 Akt 抑制剂 MK2206 可显著增加 HCC 细胞对索拉非尼的敏感性。更重要的是，HCC 组织中 p-Akt 的表达水平与 FXYD5 的表达呈正相关。因此，从机制上讲，FXYD5 通过激活 Akt/mTOR 信号通路增强了 HCC 细胞对索拉非尼的耐药性。总之，这项研究表明，FXYD5/Akt/mTOR 信号轴的激活在 HCC 细胞对索拉非尼的耐药性中起关键作用，FXYD5 可能成为 HCC 治疗的新潜在靶点。
