Modulation of Glucose Metabolism by CD44 Contributes to Antioxidant Status and Drug Resistance in Cancer Cells

TLDR

Elevated glycolysis and PPP activity contribute to chemoresistance in cancer cells. CD44 promotes glycolysis through PKM2 in p53‑deficient or hypoxic cancer cells, and its knockdown shifts metabolism to mitochondria, depletes glutathione, increases reactive oxygen species, and enhances chemosensitivity, making CD44 a potential therapeutic target. Published in Cancer Research 72(6):1438–48, ©2012 AACR.

Abstract

Abstract An increased glycolytic flux accompanied by activation of the pentose phosphate pathway (PPP) is implicated in chemoresistance of cancer cells. In this study, we found that CD44, a cell surface marker for cancer stem cells, interacts with pyruvate kinase M2 (PKM2) and thereby enhances the glycolytic phenotype of cancer cells that are either deficient in p53 or exposed to hypoxia. CD44 ablation by RNA interference increased metabolic flux to mitochondrial respiration and concomitantly inhibited entry into glycolysis and the PPP. Such metabolic changes induced by CD44 ablation resulted in marked depletion of cellular reduced glutathione (GSH) and increased the intracellular level of reactive oxygen species in glycolytic cancer cells. Furthermore, CD44 ablation enhanced the effect of chemotherapeutic drugs in p53-deficient or hypoxic cancer cells. Taken together, our findings suggest that metabolic modulation by CD44 is a potential therapeutic target for glycolytic cancer cells that manifest drug resistance. Cancer Res; 72(6); 1438–48. ©2012 AACR.