title: The EGF Receptor Promotes the Malignant Potential of Glioma by Regulating Amino Acid Transport System xc(-).
abstract: Extracellular free amino acids contribute to the interaction between a tumor and its microenvironment through effects on cellular metabolism and malignant behavior. System xc(-) is composed of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate. Here, we show that the EGFR interacts with xCT and thereby promotes its cell surface expression and function in human glioma cells. EGFR-expressing glioma cells manifested both enhanced antioxidant capacity as a result of increased cystine uptake, as well as increased glutamate, which promotes matrix invasion. Imaging mass spectrometry also revealed that brain tumors formed in mice by human glioma cells stably overexpressing EGFR contained higher levels of reduced glutathione compared with those formed by parental cells. Targeted inhibition of xCT suppressed the EGFR-dependent enhancement of antioxidant capacity in glioma cells, as well as tumor growth and invasiveness. Our findings establish a new functional role for EGFR in promoting the malignant potential of glioma cells through interaction with xCT at the cell surface. Cancer Res; 76(10); 2954-63. ©2016 AACR.
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan. Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsuchihashi
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Okazaki
authors.affiliation: Department of Biochemistry, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan. Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo, Japan.
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Ohmura
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Oltea
authors.initials: O
authors.lastname: Sampetrean
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Onishi
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Yoshikawa
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Seishima
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Iwasaki
authors.affiliation: Department of Biochemistry, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan. Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kinki University, Higashiosaka, Osaka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Abe
authors.affiliation: Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kinki University, Higashiosaka, Osaka, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Takao
authors.affiliation: Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kinki University, Higashiosaka, Osaka, Japan.
authors.forename: Misato
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kinki University, Higashiosaka, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Masuko
authors.affiliation: Department of Neurosurgery, Kyorin University Faculty of Medicine, Mitaka, Tokyo, Japan.
authors.forename: Motoo
authors.initials: M
authors.lastname: Nagane
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Furnari
authors.affiliation: Laboratory of Molecular and Genetic Information, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Akiyama
authors.affiliation: Department of Biochemistry, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan. Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO), Suematsu Gas Biology Project, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka, Japan.
authors.forename: Eishi
authors.initials: E
authors.lastname: Baba
authors.affiliation: Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan. osmna@sb3.so-net.ne.jp.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagano
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D003553:Cystine / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D017382:Reactive Oxygen Species / Q000378:metabolism; D012460:Sulfasalazine / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D027182:Amino Acid Transport System y+; D000975:Antioxidants; D017382:Reactive Oxygen Species; C118895:SLC7A11 protein, human; D018698:Glutamic Acid; D012460:Sulfasalazine; D003553:Cystine; C512478:EGFR protein, human; D066246:ErbB Receptors