Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle
Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle
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Skp2 决定糖酵解和 TCA 循环之间的细胞周期依赖性代谢振荡
DOI：
10.1038/s41422-020-0372-z
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发表时间：
2020-07-15
期刊：
影响因子：
44.1
通讯作者：
Wei, Wenyi
中科院分区：
文献类型：
--
作者：
Liu, Jing;Peng, Yunhua;Wei, Wenyi
葡萄糖主要通过氧化磷酸化或糖酵解代谢，在静止细胞与增殖细胞（包括肿瘤细胞）之间存在差异。然而，在哺乳动物细胞中，葡萄糖代谢如何与细胞周期协调仍然是一个谜。在这里，我们报告说，哺乳动物细胞主要利用三羧酸（TCA）循环在G1期，但更喜欢糖酵解在S期。从机制上讲，细胞周期与代谢的偶联主要是通过Skp 2依赖性方式及时破坏关键TCA循环酶IDH 1/2来实现的。因此，depletingSKP 2消除了IDH 1蛋白丰度的细胞周期依赖性波动，导致S期糖酵解减少。此外，前列腺癌细胞中Skp 2丰度升高使IDH 1不稳定，有利于糖酵解和随后的肿瘤发生。因此，我们的研究揭示了两个癌症标志，异常细胞周期和糖酵解成瘾之间的机制联系，并提供了哺乳动物细胞中代谢波动与周期性细胞周期耦合的潜在机制。
Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells. However, how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive. Here, we report that mammalian cells predominantly utilize the tricarboxylic acid (TCA) cycle in G1 phase, but prefer glycolysis in S phase. Mechanistically, coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2, key TCA cycle enzymes, in a Skp2-dependent manner. As such, depletingSKP2abolishes cell cycle-dependent fluctuation of IDH1 protein abundance, leading to reduced glycolysis in S phase. Furthermore, elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis. Therefore, our study reveals a mechanistic link between two cancer hallmarks, aberrant cell cycle and addiction to glycolysis, and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.