xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction.
xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction.
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DOI：
10.18632/oncotarget.25794
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发表时间：
2018-08-17
期刊：
影响因子：
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通讯作者：
Timmerman LA
中科院分区：
文献类型：
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作者：
Cobler L;Zhang H;Suri P;Park C;Timmerman LA
2012年，约有300万美国癌症患者和170万欧盟癌症患者接受了多剂量放射治疗（RT），治疗持续时间受到正常邻近组织损伤的限制。肿瘤特异性敏化可以允许用较低的辐射剂量进行治疗，减少正常组织损伤。这是一个长期存在的，很大程度上未实现的治疗目标。胱氨酸：谷氨酸交换体xCT在大多数实体瘤的预后不良亚群上表达，但在大多数正常细胞上不表达。xCT为细胞提供环境胱氨酸以增强谷胱甘肽合成。Glucoside用于控制活性氧（ROS），其是RT的治疗效应物。我们测试了xCT抑制是否会使xCT+肿瘤细胞对电离辐射敏感。我们发现，在体外和异种移植物中，用xCT抑制剂erastin预处理可以有效地致敏xCT+细胞，而不是xCT−细胞。同样，靶向基因失活也致敏细胞，这两种致敏模式都被谷胱甘肽补充剂克服。致敏抑制DNA损伤信号传导，增加基因组不稳定性，并增强细胞死亡，揭示了半胱氨酸在基因组完整性维护中不可预见的作用。我们的结论是，xCT特异性治疗将提供肿瘤特异性敏化RT，允许治疗较低的辐射剂量，并产生远远少于其他拟议的敏化剂的副作用。我们的数据表明需要快速开发这种药物。
About 3 million US cancer patients and 1.7 million EU cancer patients received multiple doses of radiation therapy (RT) in 2012, with treatment duration limited by normal adjacent tissue damage. Tumor-specific sensitization could allow treatment with lower radiation doses, reducing normal tissue damage. This is a longstanding, largely unrealized therapeutic goal. The cystine:glutamate exchanger xCT is expressed on poor prognosis subsets of most solid tumors, but not on most normal cells. xCT provides cells with environmental cystine for enhanced glutathione synthesis. Glutathione is used to control reactive oxygen species (ROS), which are therapeutic effectors of RT. We tested whether xCT inhibition would sensitize xCT+ tumor cells to ionizing radiation. We found that pretreatment with the xCT inhibitor erastin potently sensitized xCT+ but not xCT− cells, in vitro and in xenograft. Similarly, targeted gene inactivation also sensitized cells, and both modes of sensitization were overcome by glutathione supplementation. Sensitization prolongs DNA damage signaling, increases genome instability, and enhances cell death, revealing an unforeseen role for cysteine in genome integrity maintenance. We conclude that an xCT-specific therapeutic would provide tumor-specific sensitization to RT, allowing treatment with lower radiation doses, and producing far fewer side effects than other proposed sensitizers. Our data speaks to the need for the rapid development of such a drug.