Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Zhejiang Province Key Laboratory of Molecular Biology in Medical Sciences, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China; Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China.
Center for Nutrition & Food Sciences, Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, Saint Lucia, Queensland, Australia.
J Biol Chem. 2024 Sep;300(9):107648. doi: 10.1016/j.jbc.2024.107648. Epub 2024 Aug 8.
Most cancer cells exhibit high glycolysis rates under conditions of abundant oxygen. Maintaining a stable glycolytic rate is critical for cancer cell growth as it ensures sufficient conversion of glucose carbons to energy, biosynthesis, and redox balance. Here we deciphered the interaction between PKM2 and the thermodynamic properties of the glycolytic pathway. Knocking down or knocking out PKM2 induced a thermodynamic equilibration in the glycolytic pathway, characterized by the reciprocal changes of the Gibbs free energy (ΔG) of the reactions catalyzed by PFK1 and PK, leading to a less exergonic PFK1-catalyzed reaction and a more exergonic PK-catalyzed reaction. The changes in the ΔGs of the two reactions cause the accumulation of intermediates, including the substrate PEP (the substrate of PK), in the segment between PFK1 and PK. The increased concentration of PEP in turn increased PK activity in the glycolytic pathway. Thus, the interaction between PKM2 and the thermodynamic properties of the glycolytic pathway maintains the reciprocal relationship between PK concentration and its substrate PEP concentration, by which, PK activity in the glycolytic pathway can be stabilized and effectively counteracts the effect of PKM2 KD or KO on glycolytic rate. In line with our previous reports, this study further validates the roles of the thermodynamics of the glycolytic pathway in stabilizing glycolysis in cancer cells. Deciphering the interaction between glycolytic enzymes and the thermodynamics of the glycolytic pathway will promote a better understanding of the flux control of glycolysis in cancer cells.
大多数癌细胞在氧供应充足的情况下表现出高糖酵解率。维持稳定的糖酵解率对于癌细胞的生长至关重要，因为它确保了足够的葡萄糖碳转化为能量、生物合成和氧化还原平衡。在这里，我们破译了 PKM2 与糖酵解途径热力学性质之间的相互作用。敲低或敲除 PKM2 会导致糖酵解途径中的热力学平衡，其特征是 PFK1 和 PK 催化的反应的吉布斯自由能 (ΔG) 的相互变化，导致 PFK1 催化的反应的放能性降低，PK 催化的反应的放能性增强。这两个反应的 ΔGs 的变化导致中间体的积累，包括 PK 的底物 PEP（PK 的底物），在 PFK1 和 PK 之间的片段中。PEP 浓度的增加反过来又增加了糖酵解途径中的 PK 活性。因此，PKM2 与糖酵解途径热力学性质之间的相互作用维持了 PK 浓度与其底物 PEP 浓度之间的相互关系，通过这种关系，可以稳定糖酵解途径中的 PK 活性，并有效地抵消 PKM2 KD 或 KO 对糖酵解率的影响。与我们之前的报告一致，这项研究进一步验证了糖酵解途径热力学在稳定癌细胞糖酵解中的作用。破译糖酵解酶与糖酵解途径热力学之间的相互作用将促进更好地理解癌细胞中糖酵解的通量控制。
