Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling.
Apatinib Promotes Ferroptosis in Colorectal Cancer Cells by Targeting ELOVL6/ACSL4 Signaling.
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DOI：
10.2147/cmar.s274631
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发表时间：
2021
影响因子：
3.3
通讯作者：
Ge G
中科院分区：
文献类型：
--
作者：
Tian X;Li S;Ge G
结直肠癌是一种常见的消化系统恶性肿瘤。铁凋亡是一种新的细胞死亡调控形式，在肿瘤的发生和治疗中起着重要作用。我们的目的是研究阿帕替尼在CRC细胞铁凋亡中的作用及其潜在机制。将人CRC HCT 116细胞暴露于阿帕替尼。使用CCK-8试剂盒检查细胞活力。使用试剂盒检测细胞内铁和活性氧（ROS）的浓度。此外，使用蛋白质印迹分析来确定铁中毒相关蛋白的表达。极长链脂肪酸家族成员6（VL 6）的延长是SwissTargetPrediction预测的阿帕替尼靶点之一。因此，在用阿帕替尼处理后评价了HPVL 6表达。随后，研究了ELOVL 6过表达对HCT 116细胞铁凋亡的影响。最后，利用STRING数据库预测了与VL 6相互作用的蛋白，并通过免疫共沉淀（co-IP）实验进行了验证。结果表明，阿帕替尼降低细胞活力，增加细胞内铁活性氧的含量。此外，阿帕替尼暴露后，观察到ACSL 4表达显著上调，同时GPx 4和FTH 1表达显著下调。此外，HCT 116细胞中的HCTVL 6表达显著增强，而在阿帕替尼干预下，HCT 116细胞中的HCTVL 6表达被显著抑制。HPVL 6过表达逆转了阿帕替尼对HCT 116细胞的细胞活力和铁凋亡的影响。此外，ACSL 4，一个重要的调节铁凋亡，可以直接相互作用，这是由co-IP的结果证实的BCLVL 6。这些结果表明，阿帕替尼通过靶向
Colorectal cancer (CRC) is a common digestive system malignancy. Ferroptosis, a new form of regulated cell death, plays a vital role in the pathogenesis and therapy of cancers. We aimed to study the role of apatinib in ferroptosis of CRC cells and its potential mechanisms. Human CRC HCT116 cells were exposed to apatinib. Cell viability was examined using a CCK-8 kit. The concentrations of intracellular iron and reactive oxygen species (ROS) were detected using kits. Additionally, Western blot analysis was used to determine the expression of ferroptosis-related proteins. Elongation of very long-chain fatty acids family member 6 (ELOVL6) was one of the targets of apatinib predicted by SwissTargetPrediction. Therefore, ELOVL6 expression was evaluated after treatment with apatinib. Subsequently, the effects of ELOVL6 overexpression on ferroptosis of HCT116 cells were investigated. Finally, STRING database was applied to predict the potential proteins interacting with ELOVL6, and co-immunoprecipitation (co-IP) assay was applied for confirmation. Results indicated that apatinib decreased cell viability and increased the contents of intracellular iron ROS. Moreover, significantly upregulated ACSL4 expression was observed, accompanied by notable downregulation of GPx4 and FTH1 expression after apatinib exposure. Furthermore, ELOVL6 expression was remarkably enhanced in HCT116 cells, which was dramatically inhibited under apatinib intervention. ELOVL6 overexpression reversed the effects of apatinib on cell viability and ferroptosis of HCT116 cells. Moreover, ACSL4, a vital regulator of ferroptosis, could interact with ELOVL6 directly, which was confirmed by the result of co-IP. These findings demonstrated that apatinib promoted ferroptosis in CRC cells by targeting ELOVL6/ACSL4, providing a new mechanism support for apatinib application in the clinical treatment of CRC.