谷氨酰胺是快速增殖细胞的关键代谢物，因为它用于合成细胞生长和增殖所需的关键代谢物。谷氨酰胺代谢已被提议作为癌症的治疗靶点，并且几种化学抑制剂正在开发或临床试验中。当谷氨酰胺受到限制时，细胞如何生存尚不清楚。在这里，通过无偏筛选，我们鉴定出编码 P5CS（脯氨酸生物合成途径中的限速酶）的 ALDH18A1 是细胞响应谷氨酰胺饥饿而下调的基因。值得注意的是，P5CS 下调促进谷氨酰胺从头合成，凸显了以前未被认识到的癌细胞代谢可塑性。因减少脯氨酸合成而保留的谷氨酸使细胞能够在谷氨酰胺限制的条件下产生细胞生存和增殖所需的关键代谢物。我们的研究结果揭示了癌细胞在营养压力下获得的适应性途径，将脯氨酸生物合成确定为以前未被认识到的谷氨酸的主要消耗者，这一途径可用于开发有效的代谢驱动的抗癌疗法。© 2023。作者，获得施普林格自然有限公司的独家许可。

Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized metabolic plasticity of cancer cells. The glutamate conserved from reducing proline synthesis allows cells to produce the key metabolites necessary for cell survival and proliferation under glutamine-restricted conditions. Our findings reveal an adaptive pathway that cancer cells acquire under nutrient stress, identifying proline biosynthesis as a previously unrecognized major consumer of glutamate, a pathway that could be exploited for developing effective metabolism-driven anticancer therapies.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.