CD44 Variant Regulates Redox Status in Cancer Cells by Stabilizing the xCT Subunit of System xc- and Thereby Promotes Tumor Growth

Takatsugu Ishimoto; Osamu Nagano; Toshifumi Yae; Mayumi Tamada; Takeshi Motohara; Hiroko Oshima; Masanobu Oshima; Tatsuya Ikeda; Rika Asaba; Hideki Yagi; Takashi Masuko; Takatsune Shimizu; Tomoki Ishikawa; Kazuharu Kai; Eri Takahashi; Yu Imamura; Yoshifumi Baba; Mitsuyo Ohmura; Makoto Suematsu; Hideo Baba; Hideyuki Saya

doi:10.1016/j.ccr.2011.01.038

CD44 Variant Regulates Redox Status in Cancer Cells by Stabilizing the xCT Subunit of System xc- and Thereby Promotes Tumor Growth

Takatsugu Ishimoto, Osamu Nagano, Toshifumi Yae, Mayumi Tamada, Takeshi Motohara, Hiroko Oshima, Masanobu Oshima, Tatsuya Ikeda, Rika Asaba, Hideki Yagi, Takashi Masuko, Takatsune Shimizu, Tomoki Ishikawa, Kazuharu Kai, Eri Takahashi, Yu Imamura, Yoshifumi Baba, Mitsuyo Ohmura, Makoto Suematsu, Hideo BabaHideyuki Saya

Breast Medical Oncology

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

942 Scopus citations

Abstract

CD44 is an adhesion molecule expressed in cancer stem-like cells. Here, we show that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level of reduced glutathione (GSH). Human gastrointestinal cancer cells with a high level of CD44 expression showed an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS). Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer. It also induced activation of p38^MAPK, a downstream target of ROS, and expression of the gene for the cell cycle inhibitor p21^CIP1/WAF1. These findings establish a function for CD44v in regulation of ROS defense and tumor growth.

Original language	English (US)
Pages (from-to)	387-400
Number of pages	14
Journal	Cancer cell
Volume	19
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2011.01.038
State	Published - Mar 8 2011

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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10.1016/j.ccr.2011.01.038

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Ishimoto, T., Nagano, O., Yae, T., Tamada, M., Motohara, T., Oshima, H., Oshima, M., Ikeda, T., Asaba, R., Yagi, H., Masuko, T., Shimizu, T., Ishikawa, T., Kai, K., Takahashi, E., Imamura, Y., Baba, Y., Ohmura, M., Suematsu, M., ... Saya, H. (2011). CD44 Variant Regulates Redox Status in Cancer Cells by Stabilizing the xCT Subunit of System xc- and Thereby Promotes Tumor Growth. Cancer cell, 19(3), 387-400. https://doi.org/10.1016/j.ccr.2011.01.038

Ishimoto, T, Nagano, O, Yae, T, Tamada, M, Motohara, T, Oshima, H, Oshima, M, Ikeda, T, Asaba, R, Yagi, H, Masuko, T, Shimizu, T, Ishikawa, T, Kai, K, Takahashi, E, Imamura, Y, Baba, Y, Ohmura, M, Suematsu, M, Baba, H & Saya, H 2011, 'CD44 Variant Regulates Redox Status in Cancer Cells by Stabilizing the xCT Subunit of System xc- and Thereby Promotes Tumor Growth', Cancer cell, vol. 19, no. 3, pp. 387-400. https://doi.org/10.1016/j.ccr.2011.01.038

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title = "CD44 Variant Regulates Redox Status in Cancer Cells by Stabilizing the xCT Subunit of System xc- and Thereby Promotes Tumor Growth",

abstract = "CD44 is an adhesion molecule expressed in cancer stem-like cells. Here, we show that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level of reduced glutathione (GSH). Human gastrointestinal cancer cells with a high level of CD44 expression showed an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS). Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer. It also induced activation of p38MAPK, a downstream target of ROS, and expression of the gene for the cell cycle inhibitor p21CIP1/WAF1. These findings establish a function for CD44v in regulation of ROS defense and tumor growth.",

author = "Takatsugu Ishimoto and Osamu Nagano and Toshifumi Yae and Mayumi Tamada and Takeshi Motohara and Hiroko Oshima and Masanobu Oshima and Tatsuya Ikeda and Rika Asaba and Hideki Yagi and Takashi Masuko and Takatsune Shimizu and Tomoki Ishikawa and Kazuharu Kai and Eri Takahashi and Yu Imamura and Yoshifumi Baba and Mitsuyo Ohmura and Makoto Suematsu and Hideo Baba and Hideyuki Saya",

note = "Funding Information: We thank I. Ishimatsu, N. Suzuki, Y. Ito, and M. Nakata for technical assistance; K. Arai for help in preparation of the manuscript; M. Fujiwara (Core Instrumentation Facility, Keio University School of Medicine) for assistance with microarray analysis; and S. Suzuki (Department of physiology, Keio University School of Medicine) for technical assistance with flow cytometric analysis. CE-MS analysis was performed by T. Matsu-ura, a technical assistant supported by the ERATO Gas Biology Project of the Japan Science and Technology Agency (JST). M.S. is the leader of the ERATO Gas Biology Project. This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to O.N. and H.S.) as well as in part by the “Academic Frontier” Project (2005–2007) and “Antiaging Center” Project (2008–2012) matching fund subsidies for private universities from the Ministry of Education, Culture, Sports, Science, and Technology and by the “A-STEP (Adaptable and Seamless Technology Transfer Program through R&D)” Project (2009–2011) matching fund subsidy from JST. ",

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doi = "10.1016/j.ccr.2011.01.038",

language = "English (US)",

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T1 - CD44 Variant Regulates Redox Status in Cancer Cells by Stabilizing the xCT Subunit of System xc- and Thereby Promotes Tumor Growth

AU - Ishimoto, Takatsugu

AU - Nagano, Osamu

AU - Yae, Toshifumi

AU - Tamada, Mayumi

AU - Motohara, Takeshi

AU - Oshima, Hiroko

AU - Oshima, Masanobu

AU - Ikeda, Tatsuya

AU - Asaba, Rika

AU - Yagi, Hideki

AU - Masuko, Takashi

AU - Shimizu, Takatsune

AU - Ishikawa, Tomoki

AU - Kai, Kazuharu

AU - Takahashi, Eri

AU - Imamura, Yu

AU - Baba, Yoshifumi

AU - Ohmura, Mitsuyo

AU - Suematsu, Makoto

AU - Baba, Hideo

AU - Saya, Hideyuki

N1 - Funding Information: We thank I. Ishimatsu, N. Suzuki, Y. Ito, and M. Nakata for technical assistance; K. Arai for help in preparation of the manuscript; M. Fujiwara (Core Instrumentation Facility, Keio University School of Medicine) for assistance with microarray analysis; and S. Suzuki (Department of physiology, Keio University School of Medicine) for technical assistance with flow cytometric analysis. CE-MS analysis was performed by T. Matsu-ura, a technical assistant supported by the ERATO Gas Biology Project of the Japan Science and Technology Agency (JST). M.S. is the leader of the ERATO Gas Biology Project. This work was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to O.N. and H.S.) as well as in part by the “Academic Frontier” Project (2005–2007) and “Antiaging Center” Project (2008–2012) matching fund subsidies for private universities from the Ministry of Education, Culture, Sports, Science, and Technology and by the “A-STEP (Adaptable and Seamless Technology Transfer Program through R&D)” Project (2009–2011) matching fund subsidy from JST.

PY - 2011/3/8

Y1 - 2011/3/8

N2 - CD44 is an adhesion molecule expressed in cancer stem-like cells. Here, we show that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level of reduced glutathione (GSH). Human gastrointestinal cancer cells with a high level of CD44 expression showed an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS). Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer. It also induced activation of p38MAPK, a downstream target of ROS, and expression of the gene for the cell cycle inhibitor p21CIP1/WAF1. These findings establish a function for CD44v in regulation of ROS defense and tumor growth.

AB - CD44 is an adhesion molecule expressed in cancer stem-like cells. Here, we show that a CD44 variant (CD44v) interacts with xCT, a glutamate-cystine transporter, and controls the intracellular level of reduced glutathione (GSH). Human gastrointestinal cancer cells with a high level of CD44 expression showed an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS). Ablation of CD44 induced loss of xCT from the cell surface and suppressed tumor growth in a transgenic mouse model of gastric cancer. It also induced activation of p38MAPK, a downstream target of ROS, and expression of the gene for the cell cycle inhibitor p21CIP1/WAF1. These findings establish a function for CD44v in regulation of ROS defense and tumor growth.

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JF - Cancer cell

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ER -

CD44 Variant Regulates Redox Status in Cancer Cells by Stabilizing the xCT Subunit of System xc- and Thereby Promotes Tumor Growth

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