Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, China.
Cell Res. 2021 Jan;31(1):80-93. doi: 10.1038/s41422-020-0372-z. Epub 2020 Jul 15.
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, depleting SKP2 abolishes 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.
葡萄糖是优先通过氧化磷酸化还是糖酵解代谢，这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相协调仍然难以捉摸。在这里，我们报告哺乳动物细胞在 G1 期主要利用三羧酸（TCA）循环，但在 S 期更倾向于糖酵解。从机制上讲，通过 Skp2 依赖性方式适时破坏 IDH1/2（关键的 TCA 循环酶），从而将细胞周期与代谢联系起来。因此，耗尽 SKP2 会消除 IDH1 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 Skp2 丰度的升高会使 IDH1 不稳定，从而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特征（细胞周期异常和对糖酵解的依赖）之间的机制联系，并为哺乳动物细胞中代谢波动与周期性细胞周期的偶联提供了潜在的机制。
