TY - JOUR
T1 - Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells
AU - Tamada, Mayumi
AU - Nagano, Osamu
AU - Tateyama, Seiji
AU - Ohmura, Mitsuyo
AU - Yae, Toshifumi
AU - Ishimoto, Takatsugu
AU - Sugihara, Eiji
AU - Onishi, Nobuyuki
AU - Yamamoto, Takehiro
AU - Yanagawa, Hiroshi
AU - Suematsu, Makoto
AU - Saya, Hideyuki
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/3/15
Y1 - 2012/3/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-11-3024
DO - 10.1158/0008-5472.CAN-11-3024
M3 - Article
C2 - 22293754
AN - SCOPUS:84863229429
VL - 72
SP - 1438
EP - 1448
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 6
ER -