Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
Cancer Res. 2012 Mar 15;72(6):1438-48. doi: 10.1158/0008-5472.CAN-11-3024. Epub 2012 Jan 31.
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 CD44 is a potential therapeutic target for glycolytic cancer cells that manifest drug resistance.
糖酵解通量增加伴随着磷酸戊糖途径（PPP）的激活与癌细胞的化疗耐药性有关。在这项研究中，我们发现，细胞表面标志物 CD44 与丙酮酸激酶 M2（PKM2）相互作用，从而增强了 p53 缺失或缺氧的癌细胞的糖酵解表型。通过 RNA 干扰敲除 CD44 增加了流向线粒体呼吸的代谢通量，同时抑制了糖酵解和 PPP 的进入。CD44 敲除引起的这种代谢变化导致细胞内还原型谷胱甘肽（GSH）明显耗竭，并增加了糖酵解癌细胞内的活性氧水平。此外，CD44 敲除增强了 p53 缺失或缺氧的癌细胞中化疗药物的作用。总之，我们的研究结果表明，CD44 的代谢调节可能是表现出耐药性的糖酵解癌细胞的一个潜在治疗靶点。
