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.
Graphical Abstract
Highlights
► 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