Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition
Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition
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DOI：
10.7554/elife.27713
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发表时间：
2017-08-15
期刊：
影响因子：
7.7
通讯作者：
Heidan, Mathew G. Vander
中科院分区：
文献类型：
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作者：
Muir, Alexander;Danai, Laura V.;Heidan, Mathew G. Vander
许多哺乳动物癌细胞系依赖谷氨酰胺作为主要的三羧酸 (TCA) 循环回补底物来支持增殖。然而，一些在培养物中依赖谷氨酰胺回补的细胞系较少依赖谷氨酰胺分解代谢来在体内增殖。我们试图了解导致回补对谷氨酰胺差异依赖的环境差异。我们发现，与在标准组织培养条件下培养的细胞相比，在成年牛血清中培养的细胞（更好地反映了细胞体内可用的营养物质）表现出谷氨酰胺分解代谢减少和对谷氨酰胺回补的依赖减少。我们发现，单一营养素胱氨酸的水平可以解释这些不同环境背景下对谷氨酰胺的不同依赖性。此外，我们发现胱氨酸水平通过胱氨酸/谷氨酸逆向转运蛋白 xCT/SLC7A11 决定谷氨酰胺依赖性。因此，xCT/SLC7A11 表达与环境胱氨酸结合，对于增加谷氨酰胺分解代谢是必要且充分的，定义了癌症中谷氨酰胺回补和谷氨酰胺酶依赖性的重要决定因素。
Many mammalian cancer cell lines depend on glutamine as a major tri-carboxylic acid (TCA) cycle anaplerotic substrate to support proliferation. However, some cell lines that depend on glutamine anaplerosis in culture rely less on glutamine catabolism to proliferate in vivo. We sought to understand the environmental differences that cause differential dependence on glutamine for anaplerosis. We find that cells cultured in adult bovine serum, which better reflects nutrients available to cells in vivo, exhibit decreased glutamine catabolism and reduced reliance on glutamine anaplerosis compared to cells cultured in standard tissue culture conditions. We find that levels of a single nutrient, cystine, accounts for the differential dependence on glutamine in these different environmental contexts. Further, we show that cystine levels dictate glutamine dependence via the cystine/glutamate antiporter xCT/SLC7A11. Thus, xCT/SLC7A11 expression, in conjunction with environmental cystine, is necessary and sufficient to increase glutamine catabolism, defining important determinants of glutamine anaplerosis and glutaminase dependence in cancer.