Fructose-2,6-bisphosphate synthesis by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is required for the glycolytic response to hypoxia and tumor growth.
Fructose-2,6-bisphosphate synthesis by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is required for the glycolytic response to hypoxia and tumor growth.
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6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 4 (PFKFB4) 合成果糖-2,6-二磷酸是对缺氧和肿瘤生长的糖酵解反应所必需的。
DOI：
10.18632/oncotarget.2213
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发表时间：
2014-08-30
期刊：
影响因子：
--
通讯作者：
Telang S
中科院分区：
文献类型：
--
作者：
Chesney J;Clark J;Klarer AC;Imbert-Fernandez Y;Lane AN;Telang S
果糖-2,6-二磷酸（F2,6BP）是糖酵解的分流产物，它变质激活6-磷酸果糖-1激酶（PFK-1），导致葡萄糖摄取增加和糖酵解到乳酸的通量。F2,6BP浓度由四种具有不同激酶磷酸酶活性的双功能6-磷酸果糖-2激酶/果糖-2,6-双磷酸酶（PFKFB1-4）决定。PFKFB4在人类癌症中过度表达，由缺氧诱导，是几种癌细胞系生存和生长所必需的。虽然PFKFB4似乎是抗肿瘤药物开发的合理靶点，但尚不清楚其激酶或磷酸酶活性是否需要癌细胞存活。在本研究中，我们发现重组人PFKFB4激酶活性比其磷酸酶活性高4.3倍，siRNA和PFKFB4的基因组缺失会降低F2、6BP， PFKFB4过表达会增加F2、6BP，体内选择性抑制PFKFB4可显著降低F2、6BP、葡萄糖摄取和ATP。最后，我们发现PFKFB4是癌细胞在缺氧代谢反应中存活所必需的，可能是在电子传递链未完全运作时使糖酵解产生ATP。综上所述，我们的数据表明，在多种转化细胞和肿瘤中表达的PFKFB4具有合成F2,6BP的功能。我们预测，对PFKFB4激酶结构域的药理学破坏可能对治疗人类癌症具有临床应用价值。
Fructose-2,6-bisphosphate (F2,6BP) is a shunt product of glycolysis that allosterically activates 6-phosphofructo-1-kinase (PFK-1) resulting in increased glucose uptake and glycolytic flux to lactate. The F2,6BP concentration is dictated by four bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) with distinct kinase:phosphatase activities. PFKFB4 is over-expressed in human cancers, induced by hypoxia and required for survival and growth of several cancer cell lines. Although PFKFB4 appears to be a rational target for anti-neoplastic drug development, it is not clear whether its kinase or phosphatase activity is required for cancer cell survival. In this study, we demonstrate that recombinant human PFKFB4 kinase activity is 4.3-fold greater than its phosphatase activity, siRNA and genomic deletion of PFKFB4 decrease F2,6BP, PFKFB4 over-expression increases F2,6BP and selective PFKFB4 inhibition in vivo markedly reduces F2,6BP, glucose uptake and ATP. Last, we find that PFKFB4 is required for cancer cell survival during the metabolic response to hypoxia, presumably to enable glycolytic production of ATP when the electron transport chain is not fully operational. Taken together, our data indicate that the PFKFB4 expressed in multiple transformed cells and tumors functions to synthesize F2,6BP. We predict that pharmacological disruption of the PFKFB4 kinase domain may have clinical utility for the treatment of human cancers.
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