TY - JOUR
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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U2 - 10.1016/j.ccr.2011.01.038
DO - 10.1016/j.ccr.2011.01.038
M3 - Article
C2 - 21397861
AN - SCOPUS:79952528125
SN - 1535-6108
VL - 19
SP - 387
EP - 400
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -
