Kiesel Violet A, Sheeley Madeline P, Donkin Shawn S, Wendt Michael K, Hursting Stephen D, Teegarden Dorothy
Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA.
Department of Animal Science, Purdue University, West Lafayette, IN 47907, USA.
Metabolites. 2022 May 23;12(5):469. doi: 10.3390/metabo12050469.
Several cancers, including breast cancers, show dependence on glutamine metabolism. The purpose of the present study was to determine the mechanistic basis and impact of differential glutamine metabolism in nonmetastatic and metastatic murine mammary cancer cells. Universally labeled C-glutamine metabolic tracing, qRT-PCR, measures of reductive-oxidative balance, and exogenous ammonium chloride treatment were used to assess glutamine reprogramming. Results show that 4 mM media concentration of glutamine, compared with 2 mM, reduced viability only in metastatic cells, and that this decrease in viability was accompanied by increased incorporation of glutamine-derived carbon into the tricarboxylic acid (TCA) cycle. While increased glutamine metabolism in metastatic cells occurred in tandem with a decrease in the reduced/oxidized glutathione ratio, treatment with the antioxidant molecule N-acetylcysteine did not rescue cell viability. However, the viability of metastatic cells was more sensitive to ammonium chloride treatment compared with nonmetastatic cells, suggesting a role of metabolic reprogramming in averting nitrogen cytotoxicity in nonmetastatic cells. Overall, these results demonstrate the ability of nonmetastatic cancer cells to reprogram glutamine metabolism and that this ability may be lost in metastatic cells.
包括乳腺癌在内的几种癌症都表现出对谷氨酰胺代谢的依赖性。本研究的目的是确定非转移性和转移性小鼠乳腺癌细胞中谷氨酰胺代谢差异的机制基础及其影响。采用通用标记的¹³C-谷氨酰胺代谢示踪、qRT-PCR、氧化还原平衡测定和外源性氯化铵处理来评估谷氨酰胺重编程。结果表明，与2 mM相比，4 mM培养基浓度的谷氨酰胺仅降低了转移性细胞的活力，且这种活力下降伴随着谷氨酰胺衍生碳进入三羧酸（TCA）循环的增加。虽然转移性细胞中谷氨酰胺代谢增加与还原型/氧化型谷胱甘肽比值降低同时发生，但用抗氧化分子N-乙酰半胱氨酸处理并不能挽救细胞活力。然而，与非转移性细胞相比，转移性细胞的活力对氯化铵处理更敏感，这表明代谢重编程在避免非转移性细胞中的氮细胞毒性方面发挥了作用。总体而言，这些结果证明了非转移性癌细胞重编程谷氨酰胺代谢的能力，而这种能力在转移性细胞中可能会丧失。
