Cystine uptake through the cystine/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation
Cystine uptake through the cystine/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation
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DOI：
10.1074/jbc.m117.814392
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发表时间：
2017-12-01
影响因子：
4.8
通讯作者：
Katoh, Hironori
中科院分区：
文献类型：
--
作者：
Goji, Takeo;Takahara, Kazuhiko;Katoh, Hironori
癌细胞中的致癌信号改变葡萄糖的摄取和利用，以提供足够的能量和生物合成中间体用于生存和持续增殖。致癌信号还防止由活性氧产生增加引起的氧化应激和细胞死亡。然而，在癌细胞中，特别是在胶质母细胞瘤中，升高的葡萄糖代谢导致细胞变得对葡萄糖剥夺敏感（即，高度葡萄糖依赖性），这迅速诱导细胞死亡。然而，这种类型的细胞死亡的确切机制仍然未知。在这里，我们报告说，葡萄糖剥夺单独不会引发胶质母细胞瘤细胞死亡。我们发现，对于在葡萄糖剥夺的胶质母细胞瘤细胞中发生的细胞死亡，胱氨酸和谷氨酰胺也需要存在于培养基中。我们观察到在葡萄糖剥夺下通过胱氨酸/谷氨酸反向转运体xCT的胱氨酸摄取迅速诱导NADPH耗尽、活性氧簇积累和细胞死亡。我们的结论是，虽然胱氨酸的摄取是至关重要的抗氧化剂谷胱甘肽在癌细胞中的生产，其通过xCT的运输也诱导氧化应激和细胞死亡的葡萄糖剥夺胶质母细胞瘤细胞。将靶向癌症特异性葡萄糖代谢的抑制剂与胱氨酸和谷氨酰胺治疗相结合，可以为表现出高xCT表达的胶质母细胞瘤肿瘤提供治疗方法。
Oncogenic signaling in cancer cells alters glucose uptake and utilization to supply sufficient energy and biosynthetic intermediates for survival and sustained proliferation. Oncogenic signaling also prevents oxidative stress and cell death caused by increased production of reactive oxygen species. However, elevated glucose metabolism in cancer cells, especially in glioblastoma, results in the cells becoming sensitive to glucose deprivation (i.e. in high glucose dependence), which rapidly induces cell death. However, the precise mechanism of this type of cell death remains unknown. Here, we report that glucose deprivation alone does not trigger glioblastoma cell death. We found that, for cell death to occur in glucose-deprived glioblastoma cells, cystine and glutamine also need to be present in culture media. We observed that cystine uptake through the cystine/glutamate antiporter xCT under glucose deprivation rapidly induces NADPH depletion, reactive oxygen species accumulation, and cell death. We conclude that although cystine uptake is crucial for production of antioxidant glutathione in cancer cells its transport through xCT also induces oxidative stress and cell death in glucose-deprived glioblastoma cells. Combining inhibitors targeting cancer-specific glucose metabolism with cystine and glutamine treatment may offer a therapeutic approach for glioblastoma tumors exhibiting high xCT expression.