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.

No abstract

ctive migration of tumor cells in extracellular matrix (ECM) is a prerequisite for tumor-cell invasion and metastasis. Specific membrane glycoproteins termed cell adhesion molecules, in addition to their basic role in cell-cell contact or cell-matrix interaction, were recently shown to be involved in more complex intracellular events, such as cell motility and gene transcription. CD44 is one of the adhesion molecules, and its importance with respect to tumor-cell invasion and metastasis has become increasingly clear. CD44 is a type I transmembrane protein and functions as the major cellular adhesion molecule for hyaluronic acid (HA), a component of ECM (Fig. 1). The extracellular domain (ectodomain) of CD44 interacts with ECM, and the intracellular domain associates with the actin cytoskeleton via binding to ERM (ezrin, radixin, and moesin) proteins. Thus, CD44 is an important mediator in regulating interaction between ECM and the intracellular actin cytoskeleton. CD44 is expressed in most human cell types and is implicated in a wide variety of physiological and pathological processes, including lymphocyte homing and activation, wound healing, and cell migration, as well as tumor cell growth and metastasis. 1-4)The proteolytic cleavage of membrane proteins including CD44 has recently emerged as a key mechanism underlying their functional regulation. Here, we aim to give a brief overview of CD44, focusing especially on the regulation of the sequential cleavages of CD44 and its biological significance. An understanding of CD44 cleavage could provide new therapeutic targets for tumor invasion and metastasis. Ectodomain cleavage of CD44 is highly prevalent in human tumorsIt was previously reported that in patients with gastric and colon cancers and malignant lymphoma, sCD44 level in the serum correlates with the tumor burden and decreases after resection of the tumor or after chemotherapy. 5,6) The major mechanism inducing the production of sCD44 is the proteolytic cleavage of the ectodomain of CD44.7) The release of the soluble ectodomain of CD44 from the membrane-bound COOHterminal fragment (CD44EXT) is responsible for dynamic regulation of the interaction between CD44 and the ECM during cell migration on an HA-containing substratum.7, 8) Highly aggressive melanoma cell lines were found to shed significant amounts of CD44 from the cell surface and to show increased CD44 synthesis as compared to other cell lines and melanocytes, 9) indicating that up-regulated turnover of CD44 may confer an invasive phenotype on these cells. Immunoblot analysis of various human cancer tissues by using an antibody specific for the intracellular domain of CD44 (anti-CD44cyto antibody) revealed that CD44 ectodomain cleavage was detected in 58% of gliomas, 67% of breast carcinomas, 45% of non-small cell lung carcinomas, 90% of colon carcinomas, and 25% of ovarian carcinomas.10) These data suggest that ectodomain cleavage of CD44 is involved in the malignancy of human tumors. Soluble form of CD44 affects the function of membrane-bound ...

In cancer metastasis, various environmental stressors attack the disseminating cells. The successful colonization of cancer cells in secondary sites therefore requires the ability of the cells to avoid the consequences of such exposure to the stressors. Here we show that orthotopic transplantation of a CD44 variant isoform-expressing (CD44v + ) subpopulation of 4T1 breast cancer cells, but not that of a CD44v − subpopulation, in mice results in efficient lung metastasis accompanied by expansion of stem-like cancer cells. such metastasis is dependent on the activity of the cystine transporter xCT, and the stability of this protein is controlled by CD44v. We find that epithelial splicing regulatory protein 1 regulates the expression of CD44v, and knockdown of epithelial splicing regulatory protein 1 in CD44v + cells results in an isoform switch from CD44v to CD44 standard (CD44s), leading to reduced cell surface expression of xCT and suppression of lung colonization. The epithelial splicing regulatory protein 1-CD44v-xCT axis is thus a potential therapeutic target for the prevention of metastasis.