Limits of aerobic metabolism in cancer cells.
Limits of aerobic metabolism in cancer cells.
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DOI：
10.1038/s41598-017-14071-y
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发表时间：
2017-10-18
影响因子：
4.6
通讯作者：
Vazquez A
中科院分区：
文献类型：
--
作者：
Fernandez-de-Cossio-Diaz J;Vazquez A
癌细胞表现出高速率的糖酵解和谷氨酰胺解。糖酵解可提供能量，谷氨酰胺解可提供碳，用于修复和柠檬酸还原羧化。然而，所有这些代谢需求原则上都可以由葡萄糖来满足。在这里，我们研究了为什么癌细胞不能通过葡萄糖的有氧生物合成来满足它们的代谢需求。基于哺乳动物细胞的典型组成，我们量化了能量需求和细胞生物合成葡萄糖的氧化磷负担。我们的计算表明，葡萄糖的有氧生长在最小加倍时间内是可行的，该时间与OxPhos负荷成正比，与线粒体OxPhos容量成反比。为了生长得更快，癌细胞必须激活有氧糖酵解以产生能量，并从生物合成中解耦产生NADH。为了使生物合成与NADH的产生脱钩，癌细胞可以从分解代谢中不产生NADH的碳源合成脂质，包括乙酸和谷氨酸、谷氨酰胺、苯丙氨酸和酪氨酸等氨基酸。最后，我们发现癌细胞系的OxPhos能力不足以支持葡萄糖的有氧生物合成。我们得出结论，选择高生物合成速率意味着选择由NADH生成的有氧糖酵解和解偶联生物合成。
Cancer cells exhibit high rates of glycolysis and glutaminolysis. Glycolysis can provide energy and glutaminolysis can provide carbon for anaplerosis and reductive carboxylation to citrate. However, all these metabolic requirements could be in principle satisfied from glucose. Here we investigate why cancer cells do not satisfy their metabolic demands using aerobic biosynthesis from glucose. Based on the typical composition of a mammalian cell we quantify the energy demand and the OxPhos burden of cell biosynthesis from glucose. Our calculation demonstrates that aerobic growth from glucose is feasible up to a minimum doubling time that is proportional to the OxPhos burden and inversely proportional to the mitochondria OxPhos capacity. To grow faster cancer cells must activate aerobic glycolysis for energy generation and uncouple NADH generation from biosynthesis. To uncouple biosynthesis from NADH generation cancer cells can synthesize lipids from carbon sources that do not produce NADH in their catabolism, including acetate and the amino acids glutamate, glutamine, phenylalanine and tyrosine. Finally, we show that cancer cell lines have an OxPhos capacity that is insufficient to support aerobic biosynthesis from glucose. We conclude that selection for high rate of biosynthesis implies a selection for aerobic glycolysis and uncoupling biosynthesis from NADH generation.
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影响因子：
2.9
作者：
Sheikh, K;Förster, J;Nielsen, LK
通讯作者：
Nielsen, LK
影响因子：
5.5
作者：
Conley, KE;Kushmerick, MJ;Jubrias, SA
通讯作者：
Jubrias, SA
影响因子：
4.1
作者：
BRAND, K
通讯作者：
BRAND, K
影响因子：
--
作者：
Vazquez A;Liu J;Zhou Y;Oltvai ZN
通讯作者：
Oltvai ZN
影响因子：
5.9
作者：
Kamphorst JJ;Chung MK;Fan J;Rabinowitz JD
通讯作者：
Rabinowitz JD