Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner
Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner
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DOI：
10.1038/s41598-019-55296-3
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发表时间：
2019-12-10
影响因子：
4.6
通讯作者：
Aoki, Shigeki
中科院分区：
文献类型：
--
作者：
Shiratori, Reika;Furuichi, Kenta;Aoki, Shigeki
大多数癌细胞依靠糖酵解来产生ATP，即使有氧气。然而，仅仅抑制糖酵解不足以根除癌细胞。其中一个主要原因是癌细胞具有使其代谢适应其环境条件的潜力。在这项研究中，我们研究了当糖酵解被抑制时，癌细胞如何改变其细胞内代谢，使用PANC-1胰腺癌细胞和另外两种实体瘤细胞系A549和HeLa。我们的研究表明，糖酵解抑制细胞上调线粒体功能，并依赖氧化磷酸化（OXPHOS），以获得生存所必需的ATP。还观察到细胞内代谢谱的动态变化，反映在TCA循环中间体水平降低和大多数氨基酸水平升高。谷氨酰胺和谷氨酸对于这种代谢重编程很重要，因为当糖酵解途径被抑制时，这些物质在很大程度上被流入TCA循环中消耗。在重编程过程中，激活的自噬参与调节线粒体功能。我们的结论是，在多种类型的肿瘤细胞的糖酵解抑制，细胞内的能量代谢重新编程向线粒体OXPHOS在自噬依赖的方式，以确保细胞的生存。
Most cancer cells rely on glycolysis to generate ATP, even when oxygen is available. However, merely inhibiting the glycolysis is insufficient for the eradication of cancer cells. One main reason for this is that cancer cells have the potential to adapt their metabolism to their environmental conditions. In this study, we investigated how cancer cells modify their intracellular metabolism when glycolysis is suppressed, using PANC-1 pancreatic cancer cells and two other solid tumor cell lines, A549 and HeLa. Our study revealed that glycolytically suppressed cells upregulated mitochondrial function and relied on oxidative phosphorylation (OXPHOS) to obtain the ATP necessary for their survival. Dynamic changes in intracellular metabolic profiles were also observed, reflected by the reduced levels of TCA cycle intermediates and elevated levels of most amino acids. Glutamine and glutamate were important for this metabolic reprogramming, as these were largely consumed by influx into the TCA cycle when the glycolytic pathway was suppressed. During the reprogramming process, activated autophagy was involved in modulating mitochondrial function. We conclude that upon glycolytic suppression in multiple types of tumor cells, intracellular energy metabolism is reprogrammed toward mitochondrial OXPHOS in an autophagy-dependent manner to ensure cellular survival.