Nutritional intervention is becoming more prevalent as adjuvant therapy for many cancers in view of tumor dependence on external sources for some nutrients. We report the dependence of glioma cells on exogenous cysteine/cystine, despite this amino acid being nonessential. 13C-tracing and the analysis of cystathionine synthase and cystathioninase levels revealed the metabolic landscape attributable to cysteine deprivation, and the disconnection between the methionine cycle and the transsulfuration pathway. Therefore, we explored the nutritional deprivation in a mouse model of glioma. Animals subjected to a cysteine/cystine-free diet survived longer, with concomitant reductions in glutathione and cysteine plasma levels. At the end point, however, tumors displayed the ability to synthesize glutathione, although higher levels of oxidative stress were detected. We observed a compensation from the nutritional intervention revealed as the recovery of cysteine-related metabolites in plasma. Our study highlights a time window where cysteine deprivation can be exploited for additional therapeutic strategies.

中文翻译：

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半胱氨酸是神经胶质瘤增殖和存活的限制因素

考虑到肿瘤对某些营养素的依赖，营养干预作为许多癌症的辅助治疗正变得越来越普遍。我们报告了神经胶质瘤细胞对外源半胱氨酸/胱氨酸的依赖性，尽管该氨基酸不是必需的。13 C跟踪和对胱硫醚合酶和胱硫醚酶水平的分析揭示了归因于半胱氨酸剥夺的蛋白质代谢，以及蛋氨酸循环与转硫途径之间的脱节。因此，我们探索了神经胶质瘤小鼠模型中的营养剥夺。接受半胱氨酸/无胱氨酸饮食的动物存活时间更长，同时谷胱甘肽和半胱氨酸血浆水平降低。然而，到最后，肿瘤表现出了合成谷胱甘肽的能力，尽管检测到较高水平的氧化应激。我们观察到营养干预中的补偿显示为血浆中半胱氨酸相关代谢产物的恢复。我们的研究突出了一个时间窗口，其中半胱氨酸剥夺可以用于其他治疗策略。