谷氨酰胺代谢途径在肿瘤化疗耐药中的功能机制

肿瘤细胞代谢重编程表现为对谷氨酰胺等营养物质摄取增加，而谷氨酰胺代谢可为在肿瘤细胞中过度激活的糖酵解和氧化磷酸化反应提供所需的原料，还可通过影响糖、脂质、蛋白质代谢的稳态平衡直接诱发肿瘤细胞对化疗药物的抵抗。针对谷氨酰胺代谢途径不同环节的抑制剂联合常规化疗药物在多种耐药肿瘤中取得了较好的临床治疗效果。谷氨酰胺代谢途径主要通过以下几种方式在肿瘤细胞耐药中发挥作用：谷氨酰胺转运体活性动态变化直接影响细胞内谷氨酰胺含量而影响细胞耐药性；肿瘤微环境中脂肪细胞、成纤维细胞及微环境代谢物通过免疫应答等方式介导耐药发生；谷氨酰胺代谢途径关键酶的表达及活性改变对肿瘤细胞耐药性的产生也至关重要。本文从转运体、肿瘤微环境及代谢酶等层面总结了谷氨酰胺代谢途径在肿瘤细胞产生化疗药物抵抗过程中的调控功能及其作用方式，以期为今后提高耐药性肿瘤的临床治疗效果提供新的思路。

Effect of glutamine metabolism on chemoresistance and its mechanism in tumors

The metabolic reprogramming of tumor cells is characterized by increased uptake of various nutrients including glutamine. Glutamine metabolism provides the required substances for glycolysis and oxidative phosphorylation and affects the homeostasis of carbohydrate，fat and protein metabolism to induce the chemoresistance of tumor cells. Combination of chemotherapeutic agents with inhibitors specific to different components of glutamine metabolic pathway has obtained favorable clinical results on various tumors. Glutamine metabolic pathway plays a role in drug resistance of tumor cells in various ways. Firstly，the dynamic change of glutamine transporters can directly affect intracellular glutamine content thereby causing drug resistance; secondly，tumor stromal cells including adipocyte，fibroblast and metabolite from tumor microenvironment would give rise to immune-mediated drug resistance; thirdly，the expression and activity of key enzymes in glutamine metabolism also has a critical role in drug resistance of tumors. This article reviews the effects of glutamine metabolic pathway in the development of tumor chemoresistance，in terms of transporters，tumor microenvironment and metabolic enzymes，to provide insight for improving the therapeutic efficacy for drug-resistant tumors.