The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-)

Kenji Tsuchihashi, Shogo Okazaki, Mitsuyo Ohmura, Miyuki Ishikawa, Oltea Sampetrean, Nobuyuki Onishi, Hiroaki Wakimoto, Momoko Yoshikawa, Ryo Seishima, Yoshimi Iwasaki, Takayuki Morikawa, Shinya Abe, Ayumi Takao, Misato Shimizu, Takashi Masuko, Motoo Nagane, Frank B. Furnari, Tetsu Akiyama, Makoto Suematsu, Eishi BabaKoichi Akashi, Hideyuki Saya, Osamu Nagano

研究成果: ジャーナルへの寄稿記事

24 引用 (Scopus)

抄録

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 inhumanglioma 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.

元の言語英語
ページ(範囲)2954-2963
ページ数10
ジャーナルCancer Research
76
発行部数10
DOI
出版物ステータス出版済み - 5 15 2016

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Amino Acid Transport Systems
Epidermal Growth Factor Receptor
Glioma
Cystine
Glutamic Acid
Antioxidants
Antiporters
Tumor Microenvironment
Brain Neoplasms
Cell Communication
Glutathione
Mass Spectrometry
Cell Membrane
Amino Acids
Growth

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-). / Tsuchihashi, Kenji; Okazaki, Shogo; Ohmura, Mitsuyo; Ishikawa, Miyuki; Sampetrean, Oltea; Onishi, Nobuyuki; Wakimoto, Hiroaki; Yoshikawa, Momoko; Seishima, Ryo; Iwasaki, Yoshimi; Morikawa, Takayuki; Abe, Shinya; Takao, Ayumi; Shimizu, Misato; Masuko, Takashi; Nagane, Motoo; Furnari, Frank B.; Akiyama, Tetsu; Suematsu, Makoto; Baba, Eishi; Akashi, Koichi; Saya, Hideyuki; Nagano, Osamu.

:: Cancer Research, 巻 76, 番号 10, 15.05.2016, p. 2954-2963.

研究成果: ジャーナルへの寄稿記事

Tsuchihashi, K, Okazaki, S, Ohmura, M, Ishikawa, M, Sampetrean, O, Onishi, N, Wakimoto, H, Yoshikawa, M, Seishima, R, Iwasaki, Y, Morikawa, T, Abe, S, Takao, A, Shimizu, M, Masuko, T, Nagane, M, Furnari, FB, Akiyama, T, Suematsu, M, Baba, E, Akashi, K, Saya, H & Nagano, O 2016, 'The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-)', Cancer Research, 巻. 76, 番号 10, pp. 2954-2963. https://doi.org/10.1158/0008-5472.CAN-15-2121
Tsuchihashi, Kenji ; Okazaki, Shogo ; Ohmura, Mitsuyo ; Ishikawa, Miyuki ; Sampetrean, Oltea ; Onishi, Nobuyuki ; Wakimoto, Hiroaki ; Yoshikawa, Momoko ; Seishima, Ryo ; Iwasaki, Yoshimi ; Morikawa, Takayuki ; Abe, Shinya ; Takao, Ayumi ; Shimizu, Misato ; Masuko, Takashi ; Nagane, Motoo ; Furnari, Frank B. ; Akiyama, Tetsu ; Suematsu, Makoto ; Baba, Eishi ; Akashi, Koichi ; Saya, Hideyuki ; Nagano, Osamu. / The EGF receptor promotes the malignant potential of glioma by regulating amino acid transport system xc(-). :: Cancer Research. 2016 ; 巻 76, 番号 10. pp. 2954-2963.
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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 inhumanglioma 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.",
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AU - Abe, Shinya

AU - Takao, Ayumi

AU - Shimizu, Misato

AU - Masuko, Takashi

AU - Nagane, Motoo

AU - Furnari, Frank B.

AU - Akiyama, Tetsu

AU - Suematsu, Makoto

AU - Baba, Eishi

AU - Akashi, Koichi

AU - Saya, Hideyuki

AU - Nagano, Osamu

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