Inhibition of the pentose phosphate pathway by dichloroacetate unravels a missing link between aerobic glycolysis and cancer cell proliferation.
Inhibition of the pentose phosphate pathway by dichloroacetate unravels a missing link between aerobic glycolysis and cancer cell proliferation.
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DOI：
10.18632/oncotarget.6272
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发表时间：
2016-01-19
期刊：
影响因子：
--
通讯作者：
Gallez B
中科院分区：
文献类型：
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作者：
De Preter G;Neveu MA;Danhier P;Brisson L;Payen VL;Porporato PE;Jordan BF;Sonveaux P;Gallez B
即使在氧气存在的情况下，通过糖酵解进行葡萄糖发酵(Warburg效应)是癌细胞的一个共同特征，越来越多地被认为是临床开发中诱人的靶点。这项研究旨在分析癌细胞的新陈代谢、能量储存和增殖率之间的联系。我们发现，在六种癌细胞系和同基因癌细胞系中，通过DNA合成定量评估细胞增殖与糖酵解效率有关。为了进一步研究糖酵解和增殖之间的联系，使用了一种戊糖磷酸途径(PPP)的药物抑制剂。我们证明了PPP活性的降低降低了癌细胞的增殖，并对Warburg表型癌细胞产生了深远的影响。利用针对葡萄糖-6-磷酸脱氢酶的siRNA证实了PPP在维持癌细胞增殖方面的关键作用，葡萄糖-6-磷酸脱氢酶是PPP的第一个也是限速酶。此外，我们发现二氯乙酸酯(DCA)，一种新的临床测试化合物，诱导糖酵解癌细胞转换为更具氧化性的表型，并抑制增殖。通过证明DCA降低PPP的活性，我们提供了一种新的DCA控制癌细胞增殖的机制。
Glucose fermentation through glycolysis even in the presence of oxygen (Warburg effect) is a common feature of cancer cells increasingly considered as an enticing target in clinical development. This study aimed to analyze the link between metabolism, energy stores and proliferation rates in cancer cells. We found that cell proliferation, evaluated by DNA synthesis quantification, is correlated to glycolytic efficiency in six cancer cell lines as well as in isogenic cancer cell lines. To further investigate the link between glycolysis and proliferation, a pharmacological inhibitior of the pentose phosphate pathway (PPP) was used. We demonstrated that reduction of PPP activity decreases cancer cells proliferation, with a profound effect in Warburg-phenotype cancer cells. The crucial role of the PPP in sustaining cancer cells proliferation was confirmed using siRNAs against glucose-6-phosphate dehydrogenase, the first and rate-limiting enzyme of the PPP. In addition, we found that dichloroacetate (DCA), a new clinically tested compound, induced a switch of glycolytic cancer cells to a more oxidative phenotype and decreased proliferation. By demonstrating that DCA decreased the activity of the PPP, we provide a new mechanism by which DCA controls cancer cells proliferation.