Modulation of Glucose Metabolism by CD44 Contributes to Antioxidant Status and Drug Resistance in Cancer Cells
Modulation of Glucose Metabolism by CD44 Contributes to Antioxidant Status and Drug Resistance in Cancer Cells
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DOI：
10.1158/0008-5472.can-11-3024
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发表时间：
2012-03-15
期刊：
影响因子：
11.2
通讯作者：
Saya, Hideyuki
中科院分区：
文献类型：
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作者：
Tamada, Mayumi;Nagano, Osamu;Saya, Hideyuki
糖酵解通量的增加伴随着戊糖磷酸途径（PPP）的激活与癌细胞的化学抗性有关。在这项研究中，我们发现，CD 44，癌症干细胞的细胞表面标志物，与丙酮酸激酶M2（PKM 2）相互作用，从而增强了p53缺陷或暴露于缺氧的癌细胞的糖酵解表型。通过RNA干扰的CD 44消融增加了线粒体呼吸的代谢通量，同时抑制了糖酵解和PPP的进入。这种由CD 44消融诱导的代谢变化导致糖酵解癌细胞中细胞还原型谷胱甘肽（GSH）的显著耗尽并增加细胞内活性氧水平。此外，CD 44消融增强了化疗药物在p53缺陷或缺氧癌细胞中的作用。综合来看，我们的发现表明。通过Call的代谢调节是表现出耐药性的糖酵解癌细胞的潜在治疗靶点。Cancer Res; 72（6）;1438-48. (C)2012年AACR
An increased glycolytic flux accompanied by activation of the pentose phosphate pathway (PPP) is implicated in chemoresistance of cancer cells. In this study, we found that CD44, a cell surface marker for cancer stem cells, interacts with pyruvate kinase M2 (PKM2) and thereby enhances the glycolytic phenotype of cancer cells that are either deficient in p53 or exposed to hypoxia. CD44 ablation by RNA interference increased metabolic flux to mitochondrial respiration and concomitantly inhibited entry into glycolysis and the PPP. Such metabolic changes induced by CD44 ablation resulted in marked depletion of cellular reduced glutathione (GSH) and increased the intracellular level of reactive oxygen species in glycolytic cancer cells. Furthermore, CD44 ablation enhanced the effect of chemotherapeutic drugs in p53-deficient or hypoxic cancer cells. Taken together, our findings suggest. that metabolic modulation by Call is a potential therapeutic target for glycolytic cancer cells that manifest drug resistance. Cancer Res; 72(6);1438-48. (C) 2012 AACR