Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8502, USA.
Nat Commun. 2017 Apr 21;8:15074. doi: 10.1038/ncomms15074.
As noted by Warburg, many cancer cells depend on the consumption of glucose. We performed a genetic screen to identify factors responsible for glucose addiction and recovered the two subunits of the xCT antiporter (system x), which plays an antioxidant role by exporting glutamate for cystine. Disruption of the xCT antiporter greatly improves cell viability after glucose withdrawal, because conservation of glutamate enables cells to maintain mitochondrial respiration. In some breast cancer cells, xCT antiporter expression is upregulated through the antioxidant transcription factor Nrf2 and contributes to their requirement for glucose as a carbon source. In cells carrying patient-derived mitochondrial DNA mutations, the xCT antiporter is upregulated and its inhibition improves mitochondrial function and cell viability. Therefore, although upregulation of the xCT antiporter promotes antioxidant defence, it antagonizes glutamine metabolism and restricts nutrient flexibility. In cells with mitochondrial dysfunction, the potential utility of xCT antiporter inhibition should be further tested.
正如 Warburg 所指出的，许多癌细胞依赖于葡萄糖的消耗。我们进行了一项遗传筛选，以确定导致葡萄糖成瘾的因素，并回收了 xCT 转运蛋白（系统 x）的两个亚基，该转运蛋白通过输出谷氨酸来为胱氨酸提供抗氧化作用。xCT 转运蛋白的破坏大大提高了葡萄糖耗尽后的细胞活力，因为谷氨酸的保留使细胞能够维持线粒体呼吸。在一些乳腺癌细胞中，xCT 转运蛋白通过抗氧化转录因子 Nrf2 上调，并有助于它们将葡萄糖作为碳源的需求。在携带患者来源的线粒体 DNA 突变的细胞中，xCT 转运蛋白上调，其抑制作用改善了线粒体功能和细胞活力。因此，尽管 xCT 转运蛋白的上调促进了抗氧化防御，但它拮抗了谷氨酰胺代谢并限制了营养物质的灵活性。在存在线粒体功能障碍的细胞中，应该进一步测试 xCT 转运蛋白抑制的潜在效用。
