Abstract 5424: CD44-mediated glucose metabolism affects ROS level and drug sensitivity in glycolytic cancer cells.

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Abstract Low reactive oxygen species (ROS) level of cancer cells is implicated in chemo-resistance. One of the reasons why cancer cells keep their ROS level low is an increased glycolytic flux accompanied by activation of pentose phosphate pathway (PPP). We found that CD44, a cell surface marker for cancer stem cells, interact with pyruvate kinase M2 (PKM2) which is one of the most important regulators of aerobic glycolysis (Warburg effect), and thereby promotes the glycolysis of cancer cells. CD44 ablation by RNA interference increased PKM2 enzymatic activity and then induced metabolic shift from glycolysis to mitochondrial respiration and concomitantly reduced glucose uptake and PPP flux via suppression of glucose transporter1 (Glut1) expression. Such metabolic changes by CD44 ablation depleted cellular reduced glutathione(GSH) contents and increased intracellular ROS level. Our group previously reported that CD44 variant expression promotes xCT-mediated cysteine uptake and consequent GSH synthesis. Taken together, we suggested that CD44 maintains GSH synthesis and low ROS level in glycolytic cancer cells not only through xCT-mediated cysteine uptake but also by maintenance of the PPP flux and consequent NADPH production. Additionally, CD44 depleted cancer cells more sensitized them anticancer drugs even in more glycolytic environments, such as p53-deficient or hypoxia, in which cancer cells show more chemo-resistance. This increased sensitivity to anticancer drugs conferred by CD44 ablation was inhibited by pretreatment with a precursor of GSH that functions as an antioxidant. Therefore, these results indicated that enhanced ROS level by CD44 ablation sensitizes highly glycolytic cancer cells to conventional chemotherapy. The possibility that CD44-targeted therapy may perturb the metabolism of cancer cells and thereby impair their capacity to defend against ROS warrants further investigation. Citation Format: Mayumi Tamada, Makoto Suematsu, Hideyuki Saya. CD44-mediated glucose metabolism affects ROS level and drug sensitivity in glycolytic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5424. doi:10.1158/1538-7445.AM2013-5424