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.
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Tamada
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagano
authors.forename: Seiji
authors.initials: S
authors.lastname: Tateyama
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Ohmura
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Yae
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugihara
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Onishi
authors.forename: Takehiro
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yanagawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
mesh_terms: D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005947:Glucose / Q000378:metabolism*; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010427:Pentose Phosphate Pathway; D011770:Pyruvate Kinase / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D011770:Pyruvate Kinase; D005978:Glutathione; D005947:Glucose