Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells
Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells
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DOI：
10.1152/ajpcell.00247.2006
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发表时间：
2007-01-01
影响因子：
5.5
通讯作者：
Ferrick, David A.
中科院分区：
文献类型：
--
作者：
Wu, Min;Neilson, Andy;Ferrick, David A.
与线粒体呼吸减少相关的葡萄糖转化为乳酸的增加是 Otto Warburg 在 20 世纪 20 年代首次描述的肿瘤的独特特征。最近的证据表明，瓦尔堡效应是由癌基因引起的，是恶性转化的潜在机制。使用一种新的体外测量细胞代谢率的方法，在两种人类癌细胞系 H460 和 A549 中研究了糖酵解增加和线粒体呼吸减少的生物能基础。通过测量细胞响应各种药理调节剂的细胞呼吸、糖酵解速率和 ATP 周转来分析生物能表型。 H460 和 A549 细胞表现出对糖酵解的依赖性，并且当其呼吸受到抑制时能够显着上调该途径。然而，事实并非如此。这些细胞系的氧化磷酸化 (OXPHOS) 能力减弱，并且当糖酵解被禁用时，无法充分上调线粒体 OXPHOS。这种观察到的线粒体损伤与对糖酵解的依赖性增加密切相关。此外，与 A549 细胞相比，H460 细胞的糖酵解程度更高，对线粒体呼吸的损害更大。最后，线粒体 ATP 合成抑制导致的糖酵解上调依赖于 AMP 激活的蛋白激酶活性。总之，我们的结果证明了这两种癌细胞系的生物能表型，其特征是糖酵解速率增加和 OXPHOS 能力的相关减弱。这些代谢改变为肿瘤细胞的生长优势和凋亡抵抗提供了机制解释。
Increased conversion of glucose to lactic acid associated with decreased mitochondrial respiration is a unique feature of tumors first described by Otto Warburg in the 1920s. Recent evidence suggests that the Warburg effect is caused by oncogenes and is an underlying mechanism of malignant transformation. Using a novel approach to measure cellular metabolic rates in vitro, the bioenergetic basis of this increased glycolysis and reduced mitochondrial respiration was investigated in two human cancer cell lines, H460 and A549. The bioenergetic phenotype was analyzed by measuring cellular respiration, glycolysis rate, and ATP turnover of the cells in response to various pharmacological modulators. H460 and A549 cells displayed a dependency on glycolysis and an ability to significantly upregulate this pathway when their respiration was inhibited. The converse, however, was not true. The cell lines were attenuated in oxidative phosphorylation (OXPHOS) capacity and were unable to sufficiently upregulate mitochondrial OXPHOS when glycolysis was disabled. This observed mitochondrial impairment was intimately linked to the increased dependency on glycolysis. Furthermore, it was demonstrated that H460 cells were more glycolytic, having a greater impairment of mitochondrial respiration, compared with A549 cells. Finally, the upregulation of glycolysis in response to mitochondrial ATP synthesis inhibition was dependent on AMP-activated protein kinase activity. In summary, our results demonstrate a bioenergetic phenotype of these two cancer cell lines characterized by increased rate of glycolysis and a linked attenuation in their OXPHOS capacity. These metabolic alterations provide a mechanistic explanation for the growth advantage and apoptotic resistance of tumor cells.