ESR1 inhibits ionizing radiation-induced ferroptosis in breast cancer cells via the NEDD4L/CD71 pathway
ESR1 inhibits ionizing radiation-induced ferroptosis in breast cancer cells via the NEDD4L/CD71 pathway
复制标题
ESR1 通过 NEDD4L/CD71 途径抑制乳腺癌细胞中电离辐射诱导的铁死亡
DOI：
10.1016/j.abb.2022.109299
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发表时间：
2022-05-24
影响因子：
3.9
通讯作者：
Liu, Xiaodong
中科院分区：
文献类型：
--
作者：
Liu, Lin;Zhang, Chen;Liu, Xiaodong
铁凋亡是一种非凋亡性细胞死亡，由铁积累和随后的脂质过氧化引起。然而，如何电离辐射（IR）诱导的铁凋亡调节雌激素受体阳性（ER+）乳腺癌细胞仍不清楚。为了试图解决这个问题，进行了生物信息学分析来评估乳腺癌组织中雌激素受体1（ESR 1）的预后价值。总共使用了四种乳腺癌细胞系和一种MCF 10A非恶性对应细胞系。蛋白质印迹法用于分析蛋白质表达水平，而免疫沉淀（IP）和泛素化实验分别用于测试蛋白质结合和泛素化水平。随后使用流式细胞术分析细胞死亡和脂质过氧化水平。结果显示，ESR 1的高表达水平与乳腺癌的总生存率显著相关。ESR 1敲低显著增强IR诱导的铁凋亡，并增加CD 71蛋白水平。IP结果显示，ESR 1增强E3泛素连接酶NEDD 4L与CD 71的结合，促进CD 71的泛素化和降解，表明CD 71的表达受ESR 1和NEDD 4L的调节。综上所述，本研究的结果表明IR诱导的铁凋亡中ESR 1和NEDD 4L/CD 71之间存在调节关系。此外，ESR 1/NEDD 4L/CD 71轴可能是乳腺癌放射治疗的潜在靶点。
Ferroptosis is the name given to the type of non-apoptotic cell death that is caused by iron accumulation and subsequent lipid peroxidation. However, how ionizing radiation (IR)-induced ferroptosis is regulated in estrogen receptor-positive (ER+) breast cancer cells remains unclear. To attempt to resolve this issue, bioinformatics analysis was performed to evaluate the prognostic value of estrogen receptor 1 (ESR1) in breast cancer tissues. A total of four breast cancer cell lines and an MCF10A non-malignant counterpart were used. Western blotting was used to analyze the levels of protein expression, whereas immunoprecipitation (IP) and ubiquitination experiments were used to test protein binding and ubiquitination levels, respectively. Flow cytometry was subsequently used to analyze cell death and lipid peroxidation levels. The results showed that a high expression level of ESR1 was significantly correlated with poor overall survival in breast cancer. ESR1 knockdown significantly enhanced IR-induced ferroptosis and increased the CD71 protein level. The IP results showed that ESR1 enhanced the binding of the E3 ubiquitin ligase NEDD4L to CD71, promoting the ubiquitination and degradation of CD71, suggesting that CD71 expression was regulated by both ESR1 and NEDD4L. Taken together, the findings in the present study have demonstrated a regulatory relationship between ESR1 and NEDD4L/CD71 in IR-induced ferroptosis. In addition, the ESR1/NEDD4L/CD71 axis may be a potential target for the radiotherapy of breast cancer.