A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells
A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells
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DOI：
10.1016/j.cmet.2019.11.020
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发表时间：
2020-02-04
期刊：
影响因子：
29
通讯作者：
Han, Jung Min
中科院分区：
文献类型：
--
作者：
Yoo, Hee Chan;Park, Seung Joon;Han, Jung Min
谷氨酰胺是一种必需的营养素，调节能量产生，氧化还原稳态和癌细胞中的信号传导。尽管谷氨酰胺在线粒体代谢中的重要性，但线粒体谷氨酰胺转运蛋白长期以来一直是未知的。在这里，我们表明SLC 1A 5变体通过将谷氨酰胺转运到线粒体中在癌症代谢重编程中起着关键作用。SLC 1A 5变体具有线粒体的N端靶向信号！本地化SLC 1A 5变体的低氧诱导的基因表达由HIF-2 α介导。SLC 1A 5变体的过表达介导谷氨酰胺诱导的ATP产生和谷胱甘肽合成，并赋予胰腺癌细胞吉西他滨抗性。SLC 1A 5变体敲低和过表达改变癌细胞和肿瘤生长，支持致癌作用。这项工作表明，SLC 1A 5变体是一种线粒体谷氨酰胺转运蛋白，用于癌症代谢重编程。
Glutamine is an essential nutrient that regulates energy production, redox homeostasis, and signaling in cancer cells. Despite the importance of glutamine in mitochondrial metabolism, the mitochondrial glutamine transporter has long been unknown. Here, we show that the SLC1A5 variant plays a critical role in cancer metabolic reprogramming by transporting glutamine into mitochondria. The SLC1A5 variant has an N-terminal targeting signal for mitochondria! localization. Hypoxia-induced gene expression of the SLC1A5 variant is mediated by HIF-2 alpha. Overexpression of the SLC1A5 variant mediates glutamine-induced ATP production and glutathione synthesis and confers gemcitabine resistance to pancreatic cancer cells. SLC1A5 variant knockdown and overexpression alter cancer cell and tumor growth, supporting an oncogenic role. This work demonstrates that the SLC1A5 variant is a mitochondrial glutamine transporter for cancer metabolic reprogramming.