Department of Medical Oncology of The Eastern Hospital, The First Affiliated Hospital, Sun Yat-Sen University, No.58, Zhong Shan Er Lu, Guangzhou 510080, China.
Department of Orthopedics, The Third Xiangya Hospital, Central South University, No. 138, Tongzipo Road, Changsha 410013, China.
Gene. 2024 Jan 20;892:147874. doi: 10.1016/j.gene.2023.147874. Epub 2023 Oct 5.
Drug resistance is an obstacle in therapy of esophageal cancers (ECs), and the role of ferroptosis in progression ECs is still not clearly clarified. In the present study, we investigated the role of Apolipoprotein C1 (Apoc1) in regulating the sorafenib resistance in EC cells. Apoc1 was knock down after infection with Apoc1 shRNA lentivirus and stable cell lines for Apoc1 knockdown were screened. Cell viabilities were tested by MTT assay. ROS, MDA, and GSH tested by specific kits. In vivo experiment in nude mice were performed to test the correlation of Apoc1 and ferroptosis. The expression of Apoc1 and GPX4 was tested by western blotting. The results showed that Apoc1 was highly expressed in EC tissues and associated with poor overall survival rate of EC. Knockdown Apoc1 overcame resistance of sorafenib in EC cells and promoted erastin and sorafenib induced ferroptosis by upregulating the levels of ROS and MDA and downregulating the level of GSH in OE19/Sora and EC109/Sora cells. Rescue experiments proved that Apoc1 regulated sorafenib induced ferroptosis via GPX4. Furthermore, knockdown of Apoc1 inhibited the tumor progression by promoting ferroptosis in nude mice. In conclusion, knockdown Apoc1 overcome resistance of sorafenib in EC cells and in vivo by promoting sorafenib induced ferroptosis via GPX4. Targeting Apoc1 might be an effective way to reverse the drug resistance of sorafenib via inducing ferroptosis in EC progression.
耐药性是食管癌细胞（ECs）治疗的障碍，铁死亡在进展期 ECs 中的作用尚不清楚。在本研究中，我们研究了载脂蛋白 C1（Apoc1）在调节 EC 细胞索拉非尼耐药中的作用。用 Apoc1 shRNA 慢病毒感染后敲低 Apoc1，筛选 Apoc1 敲低的稳定细胞系。通过 MTT 法检测细胞活力。通过特定试剂盒检测 ROS、MDA 和 GSH。在裸鼠体内实验中检测 Apoc1 与铁死亡的相关性。通过 Western blot 检测 Apoc1 和 GPX4 的表达。结果表明，Apoc1 在 EC 组织中高表达，与 EC 的总生存率差相关。敲低 Apoc1 可克服 EC 细胞对索拉非尼的耐药性，并通过上调 OE19/Sora 和 EC109/Sora 细胞中 ROS 和 MDA 的水平，下调 GSH 的水平，促进依马替尼和索拉非尼诱导的铁死亡。挽救实验证明，Apoc1 通过 GPX4 调节索拉非尼诱导的铁死亡。此外，在裸鼠中敲低 Apoc1 通过促进铁死亡抑制肿瘤进展。总之，敲低 Apoc1 通过 GPX4 促进索拉非尼诱导的铁死亡，在体内和体外克服 EC 细胞对索拉非尼的耐药性。靶向 Apoc1 可能是通过诱导铁死亡逆转 EC 进展中索拉非尼耐药的有效方法。
