CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth

Cancer Cell. 2011 Mar 8;19(3):387-400. doi: 10.1016/j.ccr.2011.01.038.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Amino Acid Transport System y+
  • Hyaluronan Receptors
  • Protein Isoforms
  • Protein Subunits
  • SLC7A11 protein, human

Associated data

  • GEO/GSE20913
  • GEO/GSE20914