An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: Role in tumor cell glycolysis and the Warburg effect
An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: Role in tumor cell glycolysis and the Warburg effect
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DOI：
10.1073/pnas.96.6.3047
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发表时间：
1999-03-16
影响因子：
11.1
通讯作者：
Bucala, R
中科院分区：
文献类型：
--
作者：
Chesney, J;Mitchell, R;Bucala, R
癌细胞即使在有氧存在的情况下也保持着较高的糖酵解速率，这一现象在70多年前首次被描述，历史上被称为沃伯格效应。果糖 -2,6 - 二磷酸是糖酵解的一种强大的变构调节剂，它能刺激6 - 磷酸果糖 -1 - 激酶（PFK -1）的活性，而PFK -1是哺乳动物糖酵解中最重要的控制点。果糖 -2,6 - 二磷酸的稳态浓度反过来取决于6 - 磷酸果糖 -2 - 激酶（PFK -2）/果糖 -2,6 - 二磷酸酶的活性，该酶以几种组织特异性异构体形式表达。我们在此报告鉴定出了这种酶的一个基因产物，它由促炎刺激诱导产生，其特征是在其3' - 非翻译末端存在多个AUUUA mRNA不稳定基序。这种可诱导的PFK -2基因在几种人类癌细胞系中组成性表达，并且发现它是肿瘤细胞在体外和体内生长所必需的。抑制可诱导的PFK -2蛋白表达会降低5 - 磷酸核糖 -1 - 焦磷酸的细胞内水平，5 - 磷酸核糖 -1 - 焦磷酸是磷酸戊糖途径的产物，也是核酸生物合成的重要前体。这些研究确定了一种可能对肿瘤生长至关重要的调节性同工酶，并为长期以来关于糖酵解增强与细胞增殖明显耦合的观察结果提供了解释。
Cancer cells maintain a high glycolytic rate even in the presence of oxygen, a phenomenon first described over 70 years ago and known historically as the Warburg effect. Fructose 2,6-bisphosphate is a powerful allosteric regulator of glycolysis that acts to stimulate the activity of 6-phosphofructo-1-kinase (PFK-1), the most important control point in mammalian glycolysis. The steady state concentration of fructose 2,6-bisphosphate in turn depends on the activity of the enzyme 6-phosphofructo-2-kinase (PFK-2)/fructose-2,6-bisphosphatase, which is expressed in several tissue-specific isoforms, We report herein the identification of a gene product for this enzyme that is induced by proinflammatory stimuli and which is distinguished by the presence of multiple copies of the AUUUA mRNA instability motif in its 3'-untranslated end. This inducible gene for PFK-2 is expressed constitutively in several human cancer cell lines and was found to be required for tumor cell growth in vitro and in vivo. Inhibition of inducible PFK-2 protein expression decreased the intracellular level of 5-phosphoribosyl-1-pyrophosphate, a product of the pentose phosphate pathway and an important precursor for nucleic acid biosynthesis. These studies identify a regulatory isoenzyme that may be essential for tumor growth and provide an explanation for long-standing observations concerning the apparent coupling of enhanced glycolysis and cell proliferation.