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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Pyruvate carboxylase is required for glutamine-independent growth of tumor cells
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Pyruvate carboxylase is required for glutamine-independent growth of tumor cells

机译：丙酮酸羧化酶是谷氨酰胺非依赖性肿瘤细胞生长所必需的

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摘要

Tumor cells require a constant supply of macromolecular precursors, and interrupting this supply has been proposed as a therapeutic strategy in cancer. Precursors for lipids, nucleic acids, and proteins are generated in the tricarboxylic acid (TCA) cycle and removed from the mitochondria to participate in biosynthetic reactions. Refilling the pool of precursor molecules (anaplerosis) is therefore crucial to maintain cell growth. Many tumor cells use glutamine to feed anaplerosis. Here we studied how "glutamine-addicted" cells react to interruptions of glutamine metabolism. Silencing of glutaminase (GLS), which catalyzes the first step in glutamine-dependent anaplerosis, suppressed but did not eliminate the growth of glioblastoma cells in culture and in vivo. Profiling metabolic fluxes in GLS-suppressed cells revealed induction of a compensatory anaplerotic mechanism catalyzed by pyruvate carboxylase (PC), allowing the cells to use glucose-derived pyruvate rather than glutamine for anaplerosis. Although PC was dispensable when glutamine was available, forcing cells to adapt to low-glutamine conditions rendered them absolutely dependent on PC for growth. Furthermore, in other cell lines, measuring PC activity in nutrient-replete conditions predicted dependence on specific anaplerotic enzymes. Cells with high PC activity were resistant to GLS silencing and did not require glutamine for survival or growth, but displayed suppressed growth when PC was silenced. Thus, PC-mediated, glucose-dependent anaplerosis allows cells to achieve glutamine independence. Induction of PC during chronic suppression of glutamine metabolism may prove to be a mechanism of resistance to therapies targeting glutaminolysis.
机译：肿瘤细胞需要持续供应大分子前体，并且已经提出中断这种供应是癌症的治疗策略。脂质，核酸和蛋白质的前体在三羧酸（TCA）循环中生成，并从线粒体中除去，参与生物合成反应。因此，重新填充前体分子库（合成代谢）对于维持细胞生长至关重要。许多肿瘤细胞使用谷氨酰胺来喂养动脉硬化。在这里，我们研究了“谷氨酰胺成瘾的”细胞对谷氨酰胺代谢中断的反应。谷氨酰胺酶（GLS）的沉默，催化了谷氨酰胺依赖性动脉粥样硬化的第一步，抑制但不能消除胶质母细胞瘤细胞在培养物中和体内的生长。在GLS抑制的细胞中分析代谢通量表明，丙酮酸羧化酶（PC）催化了一种补偿性的抗动脉粥样硬化机制，使细胞能够使用葡萄糖衍生的丙酮酸而不是谷氨酰胺来进行动脉硬化。尽管当谷氨酰胺可用时PC是可有可无的，但强迫细胞适应低谷氨酰胺条件使它们绝对依赖PC进行生长。此外，在其他细胞系中，在营养充足的条件下测量PC活性可预测对特定抗血管生成酶的依赖性。具有高PC活性的细胞对GLS沉默具有抗性，并且不需要谷氨酰胺来存活或生长，但是当PC沉默时其生长受到抑制。因此，PC介导的葡萄糖依赖性动脉粥样硬化可使细胞实现谷氨酰胺独立性。在谷氨酰胺代谢的慢性抑制过程中诱导PC可能是抵抗针对谷氨酰胺分解疗法的机制。

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