CD44 Variant Regulates Redox Status in Cancer Cells by Stabilizing the xCT Subunit of System xc- and Thereby Promotes Tumor Growth
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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DOI：
10.1016/j.ccr.2011.01.038
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发表时间：
2011-03-15
期刊：
影响因子：
50.3
通讯作者：
Saya, Hideyuki
中科院分区：
文献类型：
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作者：
Ishimoto, Takatsugu;Nagano, Osamu;Saya, Hideyuki
CD44是一种在肿瘤干细胞中表达的黏附分子。在这里，我们展示了CD44变异体(CD44v)与谷氨酸-胱氨酸转运体XCT的相互作用，并控制细胞内还原型谷胱甘肽(GSH)的水平。高表达CD44的人胃肠道癌细胞具有较强的GSH合成能力和对ROS的防御能力。在转基因小鼠胃癌模型中，去除CD44导致XCT从细胞表面丢失并抑制肿瘤生长。它还诱导ROS下游靶点p38(MAPK)的激活，以及细胞周期抑制因子p21(CIP1/WAF1)基因的表达。这些发现确立了CD44v在调节ROS防御和肿瘤生长中的作用。
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.