Koppula Pranavi, Zhang Yilei, Shi Jiejun, Li Wei, Gan Boyi
From the Departments of Experimental Radiation Oncology Houston, Texas 77030; Program of Genes and Development, University of Texas Graduate School of Biomedical Sciences, Houston, Texas 77030.
From the Departments of Experimental Radiation Oncology Houston, Texas 77030.
J Biol Chem. 2017 Aug 25;292(34):14240-14249. doi: 10.1074/jbc.M117.798405. Epub 2017 Jun 19.
Cancer cells with specific genetic alterations may be highly dependent on certain nutrients for survival, which can inform therapeutic strategies to target these cancer-specific metabolic vulnerabilities. The glutamate/cystine antiporter solute carrier family 7 member 11 (SLC7A11, also called xCT) is overexpressed in several cancers. Contrasting the established pro-survival roles of SLC7A11 under other stress conditions, here we report the unexpected finding that overexpression enhances cancer cell dependence on glucose and renders cancer cells more sensitive to glucose starvation-induced cell death and, conversely, that deficiency by either knockdown or pharmacological inhibition promotes cancer cell survival upon glucose starvation. We further show that glucose starvation induces expression through ATF4 and NRF2 transcription factors and, correspondingly, that or deficiency also renders cancer cells more resistant to glucose starvation. Finally, we show that overexpression decreases whereas deficiency increases intracellular glutamate levels because of SLC7A11-mediated glutamate export and that supplementation of α-ketoglutarate, a key downstream metabolite of glutamate, fully restores survival in -overexpressing cells under glucose starvation. Together, our results support the notion that both glucose and glutamate have important roles in maintaining cancer cell survival and uncover a previously unappreciated role of SLC7A11 to promote cancer cell dependence on glucose. Our study therefore informs therapeutic strategies to target the metabolic vulnerability in tumors with high expression.
具有特定基因改变的癌细胞可能高度依赖某些营养物质来维持生存，这可为针对这些癌症特异性代谢弱点的治疗策略提供依据。谷氨酸/胱氨酸反向转运体溶质载体家族7成员11（SLC7A11，也称为xCT）在多种癌症中过表达。与SLC7A11在其他应激条件下已确立的促生存作用形成对比的是，我们在此报告了一个意外发现：过表达会增强癌细胞对葡萄糖的依赖性，并使癌细胞对葡萄糖饥饿诱导的细胞死亡更敏感；相反，通过敲低或药物抑制使其缺乏，则会促进癌细胞在葡萄糖饥饿时的存活。我们进一步表明，葡萄糖饥饿通过激活转录因子ATF4和NRF2诱导SLC7A11的表达，相应地，SLC7A11的缺乏也使癌细胞对葡萄糖饥饿更具抗性。最后，我们表明，由于SLC7A11介导的谷氨酸输出，SLC7A11过表达会降低而其缺乏会增加细胞内谷氨酸水平，并且补充谷氨酸的关键下游代谢产物α-酮戊二酸可完全恢复SLC7A11过表达细胞在葡萄糖饥饿时的存活率。总之，我们的结果支持了葡萄糖和谷氨酸在维持癌细胞存活中都起重要作用的观点，并揭示了SLC7A11促进癌细胞对葡萄糖依赖性的一个先前未被认识的作用。因此，我们的研究为针对高表达SLC7A11的肿瘤中的代谢弱点制定治疗策略提供了依据。
