Control of Glycolytic Flux by AMP-Activated Protein Kinase in Tumor Cells Adapted to Low pH
Control of Glycolytic Flux by AMP-Activated Protein Kinase in Tumor Cells Adapted to Low pH
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DOI：
10.1593/tlo.11319
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发表时间：
2012-06-01
影响因子：
5
通讯作者：
Burd, Randy
中科院分区：
文献类型：
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作者：
Mendoza, Erin E.;Pocceschi, Michael G.;Burd, Randy
肿瘤细胞生长在缺乏营养和氧气的微环境中，通过改变代谢途径来适应次优的生长条件。这种适应过程通常导致肿瘤表型表现出高比率的有氧糖酵解和侵袭性肿瘤特征。葡萄糖调节分子6-phosphofructo-2-kinase/fructose-2，6-biphosphatase 3(PfKFB3)是一种双功能酶，是糖酵解的中心，位于代谢应激感受器AMPK的下游，已被认为调节糖酵解，并可能激活PfKFB的异构体，特别是在肿瘤细胞中表达的PfKFB3。我们的结果表明，长期低pH暴露诱导了AMPK的激活，导致PFKFB3的上调和丝氨酸残基的磷酸化增加。AMPK的药理激活导致PFKFB3表达增加，葡萄糖消耗增加，而AMPK抑制则导致PFKFB3表达下调，糖酵解减少。在DB-1肿瘤细胞中过表达PFKFB3可诱导较高的糖酵解速率，并抑制氧消耗，证实了其控制糖酵解通量的作用。这些结果表明，低pH值是一种生理应激，可以促进通常与肿瘤发生有关的糖酵解表型。结果表明，肿瘤微环境对肿瘤生长和治疗耐药有重要影响。
Tumor cells grow in nutrient- and oxygen-deprived microenvironments and adapt to the suboptimal growth conditions by altering their metabolic pathways. This adaptation process commonly results in a tumor phenotype that displays a high rate of aerobic glycolysis and aggressive tumor characteristics. The glucose regulatory molecule, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), is a bifunctional enzyme that is central to glycolytic flux and is downstream of the metabolic stress sensor AMP-activated protein kinase (AMPK), which has been suggested to modulate glycolysis and possibly activate isoforms of PFKFB, specifically PFKFB3 expressed in tumor cells. Our results demonstrated that long-term low pH exposure induced AMPK activation, which resulted in the up-regulation of PFKFB3 and an increase in its serine residue phosphorylation. Pharmacologic activation of AMPK resulted in an increase in PFKFB3 as well as an increase in glucose consumption, whereas in contrast, inhibition of AMPK resulted in the down-regulation of PFKFB3 and decreased glycolysis. PFKFB3 overexpression in DB-1 tumor cells induced a high rate of glycolysis and inhibited oxygen consumption, confirming its role in controlling glycolytic flux. These results show that low pH is a physiological stress that can promote a glycolytic phenotype commonly associated with tumorigenesis. The implications are that the tumor microenviroment contributes to tumor growth and treatment resistance.