xCT在辐射诱导的细胞损伤及铁死亡中的作用及调控机制

It is well known that ionizing radiation could increase the ROS production and change the balance between the oxidative and antioxidative systems, consequently induce radiation injury. The cystine/glutamate antiporter (system Xc −) transports cystine into cell in exchange for glutamate，consisting of CD98 and xCT, and xCT is in charge of the input of cystine and the output of glutamate, and the synthesis of glutathione. Our previous data found that xCT participated in the radiation-induced iron-dependent ROS production and ferroptosis. In this study the following aspects will be included: (1) to verify the roles of xCT in the radiation-induced ferroptosis; (2) trnascriptionally regulative mechanism: to confirm the EGR1,Nrf2 and ATF4 regulation of xCT; (3) xCT expression and the interaction between proteins: to confirm the roles of CD71-xCT and HSP90AB-xCT pathways; (4) post-trnascriptionally regulative mechanism: to confirm the roles of MEK/mTORC2 in the phosphorylation of xCT; (5) In vivo trials: to confirm the roles of xCT in the radiation killing on both normal tissues and exografts, and assess the injury and treatment efficacy. The above-mentioned research will fulfill the underlying mechanisms of radiation injury and figure out the potential targets and drugs via the suppression of ferroptosis mechanism, which show a promising theoretical value and application prospect.

电离辐射通过破坏体内氧化还原系统平衡引起细胞损伤。胱氨酸/谷氨酸反向转运体 (System Xc-)由CD98和xCT亚单位构成，CD98负责招募xCT到质膜,xCT参与谷胱甘肽(GSH) 合成和胱氨酸的跨膜穿梭，发挥抗氧化应激作用。我们研究发现，xCT参与辐射诱导的铁依赖性ROS产生和铁死亡的调控。本项目拟开展xCT调控辐射损伤和铁死亡机制研究：首先证实xCT参与辐射诱导的铁死亡过程，继而分别从转录调控（辐射敏感转录因子EGR1、Nrf2和ATF4对 xCT调控）、翻译调控（xCT与CD71、HSP90AB互做调控）、翻译后调控（MEK、mTORC2对xCT磷酸化调控）阐明xCT作用机制，最后从整体水平（动物实验、人体标本）验证xCT在辐射损伤中的作用。本研究将丰富辐射损伤及细胞死亡调控机制，通过抑制铁死亡防治辐射损伤，寻找候选靶点和药物，具有重要的理论价值和潜在的应用价值。

近年来，乳腺癌的异质性增加了其对不断变化的肿瘤微环境的适应能力，造成转移形成和治疗耐药性，这是乳腺癌治疗所面临的最大挑战。放射治疗是降低手术后乳腺癌复发风险的有效方法，几乎适用于每个阶段的患者。目前大多数乳腺癌患者通常根据手术类型和临床分期接受放射治疗，不考虑分子亚型之间的差异。然而，由于放射敏感性的个体差异，一些患者仍然无法从这种治疗中受益。因此，有必要对乳腺癌辐射抗性的机制进行深入研究，寻找辐射增敏的靶点，来提高放射治疗的有效性。本课题组前期以ER阳性乳腺癌细胞MCF-7、ZR-75和T47D为研究对象，研究发现（1）电离辐射诱导ER阳性乳腺癌细胞发生铁死亡；（2）ESR1/NEDD4L /SLC7A11通路调控辐射诱导的ER阳性乳腺癌细胞NCF-7和zr-75铁死亡；（3）ESR1/NEDD4L/CD71通路调控辐射诱导的ER阳性乳腺癌细胞T47D铁死亡；（4）lncRNA MALAT1A通过NDFIP1/NEDD4L/SLC7A11通路调控乳腺癌细胞放射敏感性；（5）lncRNA MALAT1A通过抑制DNA修复以增强乳腺癌的放射敏感性。我们的研究对ER阳性乳腺癌的临床治疗具有一定的指导意义，具有转化医学的特色。