Modulation of Glucose Metabolism by CD44 Contributes to Antioxidant Status and Drug Resistance in Cancer Cells

Mayumi Tamada,Takehiro Yamamoto,Hideyuki Saya,Toshifumi Yae,Takatsugu Ishimoto,Eiji Sugihara,Hiroshi Yanagawa,Osamu Nagano,Makoto Suematsu,Nobuyuki Onishi,Seiji Tateyama,Mitsuyo Ohmura

doi:10.1158/0008-5472.can-11-3024

Abstract

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.

Highlights

Most cancer cells depend primarily on glycolysis for their energy production regardless of the availability of oxygen
We measured the production of lactate, the final product of glycolysis, and found that CD44 ablation reduced lactate production in p53KO cells (Fig. 3B), Collectively, our results suggested that CD44 ablation induces a metabolic shift from aerobic glycolysis to mitochondrial respiration in cancer cells
Like p53 deficiency, hypoxia promotes glycolysis and confers drug resistance in cancer cells [30, 31], we investigated whether CD44 ablation affects glucose metabolism and drug sensitivity under hypoxia. p53WT cells cultured under such conditions show more of a glycolytic phenotype, including increased Glut1 expression (Supplementary Fig. S6C), glucose consumption (Fig. 6B), and lactate production (Fig. 6C), compared with those cultured under normoxia

Summary

Introduction

Most cancer cells depend primarily on glycolysis for their energy production regardless of the availability of oxygen. This unique metabolism is known as aerobic glycolysis called "Warburg effect" [1, 2]. The glycolytic energetics under mitochondrial respiratory suppression in cancer cells reduces production of reactive oxygen species (ROS) and thereby confers resistance to various therapies. Interventions to tumors for switching from glycolysis to mitochondrial respiration were found to reduce tumor mass [3], suggesting that aerobic glycolysis is an important feature of cancer cells distinct from normal cells. Precise mechanisms underlying the switch to use of glycolysis for energy production in cancer cells remain unclear. Dysfunction of p53, which frequently occurs in human cancers, promotes aerobic glycolysis, because p53 positively regulates mitochondrial respiration through inducing cyto-

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Conclusion