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

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...

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Bibliographic Details
Published in:Cancer cell 2011-03, Vol.19 (3), p.387-400
Main Authors: Ishimoto, Takatsugu, Nagano, Osamu, Yae, Toshifumi, Tamada, Mayumi, Motohara, Takeshi, Oshima, Hiroko, Oshima, Masanobu, Ikeda, Tatsuya, Asaba, Rika, Yagi, Hideki, Masuko, Takashi, Shimizu, Takatsune, Ishikawa, Tomoki, Kai, Kazuharu, Takahashi, Eri, Imamura, Yu, Baba, Yoshifumi, Ohmura, Mitsuyo, Suematsu, Makoto, Baba, Hideo, Saya, Hideyuki
Format: Article
Language:English
Subjects:
Amino Acid Transport System y+ - genetics
Amino Acid Transport System y+ - metabolism
Animals
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Cell Line, Tumor
Cell Proliferation
Female
Gene Expression Profiling
HCT116 Cells
HEK293 Cells
HT29 Cells
Humans
Hyaluronan Receptors - genetics
Hyaluronan Receptors - metabolism
Male
Mice
Mice, Knockout
Mice, Nude
Mice, Transgenic
Oxidation-Reduction
Protein Isoforms - genetics
Protein Isoforms - metabolism
Protein Stability
Protein Subunits - genetics
Protein Subunits - metabolism
RNA Interference
Stomach Neoplasms - drug therapy
Stomach Neoplasms - metabolism
Stomach Neoplasms - pathology
Tumor Burden - genetics
Xenograft Model Antitumor Assays
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Summary: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. [Display omitted] ► CD44v contributes to the reduction of intracellular reactive oxygen species ► CD44v promotes GSH synthesis by interacting with glutamate-cystine transporter xCT ► Variant 8–10 region is required for CD44v-xCT interaction leading to GSH synthesis ► xCT inhibitor sulfasalazine suppresses CD44-dependent cancer cell expansion in vivo
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2011.01.038