Glutamine Transporter SLC1A5 Regulates Ionizing Radiation-Derived Oxidative Damage and Ferroptosis.
Glutamine Transporter SLC1A5 Regulates Ionizing Radiation-Derived Oxidative Damage and Ferroptosis.
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DOI：
10.1155/2022/3403009
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发表时间：
2022
影响因子：
--
通讯作者：
Xue, Lixiang
中科院分区：
文献类型：
--
作者：
Yuan, Zhuhui;Liu, Tong;Huo, Xiao;Wang, Hao;Wang, Junjie;Xue, Lixiang
电离辐射源性氧化应激和铁死亡是破坏肝肿瘤最重要的生物学效应之一，而肝肿瘤的放射抗性仍然是放疗（RT）失败的主要原因，主要是因为保护性抗铁死亡，其中氧化应激和随后的脂质过氧化是关键引发剂。因此，克服铁死亡抵抗对于提高肝肿瘤患者放疗的治疗效果具有重要意义。通过长期暴露于X射线（2至8Gy）建立抗辐射HepG2细胞（HepG2-IRR），靶向代谢组学分析显示HepG2-IRR细胞在铁死亡应激下细胞内氨基酸明显增加。在这些变化明显的氨基酸中，N-乙酰谷氨酰胺是谷氨酰胺的衍生物，对于肿瘤细胞的氧化还原稳态和进展至关重要。有趣的是，谷氨酰胺饥饿的治疗可以显着促进铁死亡效应，而补充谷氨酰胺则完全逆转铁死亡效应。与氨基酸模式的变化一致，谷氨酰胺转运蛋白 SLC1A5 在来自 TCGA 训练和验证队列的肝脏肿瘤样本中被验证为独立的预后氨基酸铁死亡基因 (AFG)。基于 SLC1A5、SLC7A11、ASNS 和 TXNRD1 的筛查预后风险评分表明，高风险评分与较差的生存率相关。体外研究表明，SLC1A5 的敲低会导致细胞活力显着下降，并促进脂质过氧化和辐射（10Gy）引起的氧化损伤。总的来说，我们的研究结果表明，SLC1A5 可能作为铁死亡的抑制基因，并且可能是电离辐射介导效应的潜在靶标。
Ionizing radiation-derived oxidative stress and ferroptosis are one of the most important biological effects on destroying the liver tumor, whereas radioresistance of liver tumor remains a leading cause of radiotherapy (RT) failure mainly because of the protective antiferroptosis, in which oxidative stress and subsequent lipid peroxidation are the key initiators. Thus, it is of great importance to overcome ferroptosis resistance to improve the therapeutic efficacy of RT in liver tumor patients. Irradiation-resistant HepG2 cells (HepG2-IRR) were established by long-term exposure to X-ray (2 to 8 Gy), and targeted metabolomics analysis revealed an obvious increase in intracellular amino acids in HepG2-IRR cells upon ferroptosis stress. Among these amino acids with obvious changes, N-acetylglutamine, a derivative of glutamine, is essential for the redox homeostasis and progression of tumor cells. Interestingly, the treatment of glutamine starvation could promote the ferroptosis effect significantly, whereas glutamine supplementation reversed the ferroptosis effect completely. Consistent with the changes in amino acids pattern, the glutamine transporter SLC1A5 was verified in liver tumor samples from TCGA training and validation cohorts as an independent prognostic amino acid-ferroptosis gene (AFG). A risk score for screening prognosis based on the SLC1A5, SLC7A11, ASNS, and TXNRD1 demonstrated that a high-risk score was correlated with poor survival. In vitro studies had shown that the knockdown of SLC1A5 resulted in a significant decrease in cell viability and promoted lipid peroxidation and oxidative damage introduced by irradiation (10 Gy). Collectively, our findings indicated that SLC1A5 may act as a suppressor gene against ferroptosis and can be a potential target for ionizing radiation mediated effects.
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影响因子：
11.4
作者：
Ren X;Li Y;Zhou Y;Hu W;Yang C;Jing Q;Zhou C;Wang X;Hu J;Wang L;Yang J;Wang H;Xu H;Li H;Tong X;Wang Y;Du J
通讯作者：
Du J
影响因子：
8
作者：
Lei G;Zhang Y;Hong T;Zhang X;Liu X;Mao C;Yan Y;Koppula P;Cheng W;Sood AK;Liu J;Gan B
通讯作者：
Gan B
影响因子：
64.8
作者：
Jiang, Le;Kon, Ning;Li, Tongyuan;Wang, Shang-Jui;Su, Tao;Hibshoosh, Hanina;Baer, Richard;Gu, Wei
通讯作者：
Gu, Wei
Discoidin 结构域受体 1 通过调节 SLC1A5 和 mTORC1 信号通路促进肝细胞癌进展
影响因子：
6.6
作者：
Pan, Yonglong;Han, Mengzhen;Zhang, Bixiang
通讯作者：
Zhang, Bixiang
影响因子：
--
作者：
Liu S;Wu W;Chen Q;Zheng Z;Jiang X;Xue Y;Lin D
通讯作者：
Lin D