Who controls the ATP supply in cancer cells? Biochemistry lessons to understand cancer energy metabolism
Who controls the ATP supply in cancer cells? Biochemistry lessons to understand cancer energy metabolism
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DOI：
10.1016/j.biocel.2014.01.025
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发表时间：
2014-05-01
影响因子：
4
通讯作者：
Rodriguez-Enriquez, Sara
中科院分区：
文献类型：
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作者：
Moreno-Sanchez, Rafael;Marin-Hernandez, Alvaro;Rodriguez-Enriquez, Sara
应用基本的生物化学原理，这篇综述分析了与瓦尔堡假设（糖酵解是癌细胞中唯一的ATP提供者）相反的数据。尽管多年来一直被忽视，但越来越多的实验证据表明，氧化磷酸化（OxPhos）对许多癌细胞类型和各种条件下的ATP供应做出了重大贡献。被正常线粒体氧化的底物如氨基酸和脂肪酸也被癌细胞贪婪地消耗。在这方面，癌细胞代谢谷氨酰胺合成代谢的目的，而不需要一个功能性的呼吸链和OxPhos的建议进行了分析，考虑热力学和动力学方面的2-酮戊二酸异柠檬酸脱氢酶催化的还原羧化。此外，代谢控制分析（MCA）的研究应用于癌细胞的能量代谢进行重新评估。无论实验/环境条件和乳酸产生速率如何，癌症糖酵解的通量控制都是稳健的，因为它涉及相同的步骤：葡萄糖转运、己糖酶、磷酸己糖异构酶和糖原降解，所有这些步骤都在途径的开始;这些步骤与磷酸果糖激酶1一起也控制正常细胞中的糖酵解。呼吸链复合物在癌细胞中比在正常细胞中对OxPhos施加显著更高的流量控制。因此，确定癌细胞中每种途径对ATP供应的贡献和/或两种途径的通量控制分布是必要的，以便识别与正常细胞的差异，这可能导致选择性靶向癌症能量代谢的合理替代疗法的设计。(C)2014爱思唯尔有限公司版权所有。
Applying basic biochemical principles, this review analyzes data that contrasts with the Warburg hypothesis that glycolysis is the exclusive ATP provider in cancer cells. Although disregarded for many years, there is increasing experimental evidence demonstrating that oxidative phosphorylation (OxPhos) makes a significant contribution to ATP supply in many cancer cell types and under a variety of conditions. Substrates oxidized by normal mitochondria such as amino acids and fatty acids are also avidly consumed by cancer cells. In this regard, the proposal that cancer cells metabolize glutamine for anabolic purposes without the need for a functional respiratory chain and OxPhos is analyzed considering thermodynamic and kinetic aspects for the reductive carboxylation of 2-oxoglutarate catalyzed by isocitrate dehydrogenase. In addition, metabolic control analysis (MCA) studies applied to energy metabolism of cancer cells are reevaluated. Regardless of the experimental/environmental conditions and the rate of lactate production, the flux-control of cancer glycolysis is robust in the sense that it involves the same steps: glucose transport, hexolcinase, hexosephosphate isomerase and glycogen degradation, all at the beginning of the pathway; these steps together with phosphofructokinase 1 also control glycolysis in normal cells. The respiratory chain complexes exert significantly higher flux-control on OxPhos in cancer cells than in normal cells. Thus, determination of the contribution of each, pathway to ATP supply and/or the flux-control distribution of both pathways in cancer cells is necessary in order to identify differences from normal cells which may lead to the design of rational alternative therapies that selectively target cancer energy metabolism. (C) 2014 Elsevier Ltd. All rights reserved.