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

Research output: Contribution to journalArticlepeer-review

620 Citations (Scopus)

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 languageEnglish
Pages (from-to)387-400
Number of pages14
JournalCancer Cell
Volume19
Issue number3
DOIs
Publication statusPublished - 08-03-2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

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