Metabolic requirements for cancer cell proliferation.
Metabolic requirements for cancer cell proliferation.
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DOI：
10.1186/s40170-016-0156-6
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发表时间：
2016
影响因子：
5.9
通讯作者：
Stephanopoulos G
中科院分区：
文献类型：
--
作者：
Keibler MA;Wasylenko TM;Kelleher JK;Iliopoulos O;Vander Heiden MG;Stephanopoulos G
癌症代谢的研究主要致力于探索致癌转化重新连接细胞代谢以维持生长和分裂速率升高的假说。对肿瘤和癌细胞系的深入研究已经证实，许多癌症相关的代谢表型允许稳健的生长和存活;然而，很少有人注意在癌症代谢的背景下以严格的方式明确识别细胞增殖的生化要求。使用充分研究的杂交瘤细胞系作为模型，我们全面和定量地列举了在哺乳动物细胞中产生新的生物量的代谢要求;这表明ATP，NADPH，NAD+，乙酰辅酶A和氨基酸的大量生物合成需求。将这种方法扩展到丝氨酸/甘氨酸和谷氨酰胺代谢途径，分别表明丝氨酸和甘氨酸催化剂提供一碳单元合成的下限和谷氨酰胺衍生碳的显著可用性，用于单独由氮需求引起的生物合成。我们将我们的生物质组成结果整合到通量平衡分析模型中，将线粒体NADH氧化的上限设置为模拟二甲双胍治疗;这些模拟再现了几种经验观察到的代谢表型，包括增加的还原性异柠檬酸脱氢酶通量。我们的分析阐明了对中心碳代谢前体、谷氨酰胺衍生氮和辅助因子（如ATP、NADPH和NAD+）的不同需求，同时也为肿瘤中观察到的各种细胞外营养摄取行为提供了依据。总的来说，这些结果表明，化学计量的考虑如何单独可以成功地预测经验观察到的表型，并提供深入了解生化动力学的基础代谢扰动的反应。本文的在线版本（doi：10.1186/s40170-016-0156-6）包含补充材料，可供授权用户使用。
The study of cancer metabolism has been largely dedicated to exploring the hypothesis that oncogenic transformation rewires cellular metabolism to sustain elevated rates of growth and division. Intense examination of tumors and cancer cell lines has confirmed that many cancer-associated metabolic phenotypes allow robust growth and survival; however, little attention has been given to explicitly identifying the biochemical requirements for cell proliferation in a rigorous manner in the context of cancer metabolism. Using a well-studied hybridoma line as a model, we comprehensively and quantitatively enumerate the metabolic requirements for generating new biomass in mammalian cells; this indicated a large biosynthetic requirement for ATP, NADPH, NAD+, acetyl-CoA, and amino acids. Extension of this approach to serine/glycine and glutamine metabolic pathways suggested lower limits on serine and glycine catabolism to supply one-carbon unit synthesis and significant availability of glutamine-derived carbon for biosynthesis resulting from nitrogen demands alone, respectively. We integrated our biomass composition results into a flux balance analysis model, placing upper bounds on mitochondrial NADH oxidation to simulate metformin treatment; these simulations reproduced several empirically observed metabolic phenotypes, including increased reductive isocitrate dehydrogenase flux. Our analysis clarifies the differential needs for central carbon metabolism precursors, glutamine-derived nitrogen, and cofactors such as ATP, NADPH, and NAD+, while also providing justification for various extracellular nutrient uptake behaviors observed in tumors. Collectively, these results demonstrate how stoichiometric considerations alone can successfully predict empirically observed phenotypes and provide insight into biochemical dynamics that underlie responses to metabolic perturbations. The online version of this article (doi:10.1186/s40170-016-0156-6) contains supplementary material, which is available to authorized users.