The Dual Regulation Effects of ESR1/NEDD4L on SLC7A11 in Breast Cancer Under Ionizing Radiation.
The Dual Regulation Effects of ESR1/NEDD4L on SLC7A11 in Breast Cancer Under Ionizing Radiation.
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电离辐射下ESR1/NEDD4L对乳腺癌SLC7A11的双重调控作用
DOI：
10.3389/fcell.2021.772380
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发表时间：
2021
影响因子：
5.5
通讯作者：
Ma S
中科院分区：
文献类型：
--
作者：
Liu R;Liu L;Bian Y;Zhang S;Wang Y;Chen H;Jiang X;Li G;Chen Q;Xue C;Li M;Liu L;Liu X;Ma S
放射治疗是乳腺癌最重要的治疗方法之一。铁凋亡是最近认识到的以脂质过氧化为特征的调节性细胞死亡形式。然而，电离辐射（IR）是否能诱导乳腺癌中的铁凋亡及其作用机制尚不清楚。应用生物信息学分析方法筛选乳腺癌组织和正常组织中差异表达的铁凋亡相关基因。然后，使用具有不同雌激素受体（ER）表型的乳腺癌细胞系进行体外研究，包括ER阳性（MCF-7和ZR-75-1）和ER阴性（MDA-MB-231）细胞。分别用qRT-PCR和Western blotting检测8戈伊X射线照射后mRNA和蛋白水平的动态变化。免疫沉淀法（IP）用于研究蛋白质之间的相互作用。荧光素酶法分析ESR 1对SLC 7A 11的转录调控作用。BODIPY C11和台盼蓝染料分别用于测定脂质过氧化和细胞死亡。结果表明，与正常乳腺组织相比，乳腺癌组织中铁代谢相关基因SLC 7A 11的表达水平较高，且与患者的生存率相关。ESR 1与SLC 7A 11的表达呈正相关。ESR 1在IR后早期促进了SLC 7A 11的表达，ESR 1/SLC 7A 11敲低显著增强了IR诱导的ER阳性细胞的铁凋亡。IR后12 h，IP数据显示E3泛素连接酶NEDD 4L与SLC 7A 11之间的相互作用增强，随后是SLC 7A 11的泛素化和降解。因此，SLC 7A 11表达受ESR 1和NEDD 4L以相反的方式调节。我们首次阐明了ESR 1和NEDD 4L在放射治疗后共同发挥作用并最终诱导乳腺癌细胞的铁凋亡，这为指导乳腺癌的临床治疗提供了新的见解。
Radiotherapy is one of the most important treatments for breast cancer. Ferroptosis is a recently recognized form of regulated cell death that is characterized by lipid peroxidation. However, whether ionizing radiation (IR) could induce ferroptosis in breast cancer and how it works remain unknown. Bioinformatics analysis were performed to screen ferroptosis-related genes differentially expressed in breast tumor tissue and normal tissue. Then, breast cancer cell lines with different estrogen receptor (ER) phenotypes were used for studies in vitro, including ER-positive (MCF-7 and ZR-75-1) and ER-negative (MDA-MB-231) cells. The dynamic changes of mRNA and protein levels were examined after x-ray of 8 Gy by qRT-PCR and Western blotting, respectively. Immunoprecipitation (IP) was used to explore the interaction between proteins. Luciferase assay was used to analyze the transcriptional regulation effect of ESR1 on SLC7A11. BODIPY C11 and trypan blue dyes were used to determine lipid peroxidation and cell death, respectively. The result showed that the ferroptosis-related gene SLC7A11 was higher in breast cancer tissues compared with normal tissues and associated with poor survival. A positive correlation exists between ESR1 and SLC7A11 expression. ESR1 promoted SLC7A11 expression at the early stage after IR. ESR1/SLC7A11 knockdown significantly enhanced IR-induced ferroptosis in ER-positive cells. At 12 h after IR, the IP data showed the interaction between E3 ubiquitin ligase NEDD4L and SLC7A11 increased, followed by the ubiquitylation and degradation of SLC7A11. Thus, SLC7A11 expression was regulated by both ESR1 and NEDD4L, in opposite ways. For the first time, we elucidated that ESR1 and NEDD4L functioned together after radiation treatment and finally induced ferroptosis in breast cancer cells, which provides novel insight into the guidance of clinical treatment of breast cancer.
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影响因子：
5.7
作者：
Escobedo, Albert;Gomes, Tiago;Macias, Maria J.
通讯作者：
Macias, Maria J.
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
--
作者：
Stoner, M;Saville, B;Safe, S
通讯作者：
Safe, S
影响因子：
6.1
作者：
Ogluszka, Magdalena;Orzechowska, Magdalena;Bednarek, Andrzej K.
通讯作者：
Bednarek, Andrzej K.
影响因子：
5
作者：
Khan, Abbas;Ashfaq-Ur-Rehman;Wei, Dong-Qing
通讯作者：
Wei, Dong-Qing