Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells

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

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

Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells

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

Research output: Contribution to journal › Article › peer-review

207 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1438-1448
Number of pages	11
Journal	Cancer Research
Volume	72
Issue number	6
DOIs	https://doi.org/10.1158/0008-5472.CAN-11-3024
Publication status	Published - 15-03-2012
Externally published	Yes

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-11-3024

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title = "Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells",

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.",

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

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doi = "10.1158/0008-5472.CAN-11-3024",

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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

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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Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells

Abstract

All Science Journal Classification (ASJC) codes

UN SDGs

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