Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm SE-171 77, Sweden.
Institute of Environmental Medicine, Division of Toxicology, Karolinska Institutet, Box 210, Stockholm SE-171 77, Sweden; College of Veterinary Medicine, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China.
Biochim Biophys Acta Mol Cell Res. 2017 Mar;1864(3):498-506. doi: 10.1016/j.bbamcr.2016.12.016. Epub 2016 Dec 18.
Tumor cells dependence on glutamine offers a rationale for their elimination via targeting of glutamine metabolism. The aim of this work was to investigate how glutamine deprivation affects the cellular response to conventionally used anticancer drugs. To answer this question, neuroblastoma cells were pre-incubated in a glutamine-free medium and treated with cisplatin or etoposide. Obtained results revealed that glutamine withdrawal affected cellular response to therapeutic drugs in a different manner. Glutamine deprivation suppressed etoposide-induced, but markedly stimulated cisplatin-induced apoptosis. Suppression of etoposide-induced cell death correlated with a downregulation of p53 expression, which, among other functions, regulates the expression of death receptor 5, one of the activators of caspase-8. In contrast, stimulation of cisplatin-induced cell death involved reactive oxygen species-mediated downregulation of FLIP-S, an inhibitor of caspase-8. As a result, the activity of caspase-8 was stimulated causing cleavage of the pro-apoptotic protein Bid, which is involved in the permeabilization of the outer mitochondrial membrane and the release of pro-apoptotic factors, such as cytochrome c from mitochondria. Thus, suppression of glutamine metabolism can sensitize tumor cells to treatment and could be utilized for anti-cancer therapy. However, it should be done cautiously, since adverse effects may occur when combined with an inappropriate therapeutic drug.
肿瘤细胞对谷氨酰胺的依赖为通过靶向谷氨酰胺代谢来消除它们提供了一个理论依据。这项工作的目的是研究谷氨酰胺剥夺如何影响细胞对常规抗癌药物的反应。为了回答这个问题，将神经母细胞瘤细胞在无谷氨酰胺的培养基中预孵育，然后用顺铂或依托泊苷处理。结果表明，谷氨酰胺剥夺以不同的方式影响细胞对治疗药物的反应。谷氨酰胺剥夺抑制依托泊苷诱导的细胞凋亡，但明显刺激顺铂诱导的细胞凋亡。抑制依托泊苷诱导的细胞死亡与 p53 表达下调相关，p53 除其他功能外，还调节半胱天冬酶-8 的激活剂之一死亡受体 5 的表达。相反，刺激顺铂诱导的细胞死亡涉及活性氧介导的半胱天冬酶-8 抑制剂 FLIP-S 的下调。结果，半胱天冬酶-8 的活性被刺激，导致促凋亡蛋白 Bid 的裂解，Bid 参与外线粒体膜的通透性和细胞色素 c 等促凋亡因子从线粒体的释放。因此，抑制谷氨酰胺代谢可以使肿瘤细胞对治疗敏感，并可用于癌症治疗。然而，应该谨慎地进行，因为当与不适当的治疗药物联合使用时可能会出现不良反应。
