Abstract
Cancer cells display enhanced glycolysis to meet their energetic and biosynthetic demands even under normal oxygen concentrations. Recent studies have revealed that tumor suppressor p53 represses glycolysis under normoxia as a novel mechanism for tumor suppression. As a common microenvironmental stress for tumors, hypoxia drives the metabolic switch from the oxidative phosphorylation to glycolysis, which is crucial for survival and proliferation of cancer cells under hypoxia. The p53's role and mechanism in regulating glycolysis under hypoxia is poorly understood. Here, we found that p53 represses hypoxia-stimulated glycolysis in cancer cells through RRAD, a newly-identified p53 target. RRAD expression is frequently decreased in lung cancer. Ectopic expression of RRAD greatly reduces glycolysis whereas knockdown of RRAD promotes glycolysis in lung cancer cells. Furthermore, RRAD represses glycolysis mainly through inhibition of GLUT1 translocation to the plasma membrane. Under hypoxic conditions, p53 induces RRAD, which in turn inhibits the translocation of GLUT1 and represses glycolysis in lung cancer cells. Blocking RRAD by siRNA greatly abolishes p53's function in repressing glycolysis under hypoxia. Taken together, our results revealed an important role and mechanism of p53 in antagonizing the stimulating effect of hypoxia on glycolysis, which contributes to p53's function in tumor suppression.
Highlights
Metabolic alterations are a hallmark of cancer cells [1,2,3]
Results from this study showed that p53 induced RRAD expression under hypoxia, which in turn negatively regulated glycolysis driven by hypoxia through inhibition of the translocation of glucose transporter 1 (GLUT1) to the plasma membrane of cells
These results demonstrated that RRAD inhibits the GLUT1 translocation to the plasma membrane (PM), which is an important mechanism for RRAD to repress the aerobic glycolysis in cancer cells
Summary
Metabolic alterations are a hallmark of cancer cells [1,2,3]. Unlike normal cells that mainly depend upon oxidative phosphorylation to provide energy, cancer cells preferentially utilize glycolysis even under normal oxygen concentrations (normoxia). Recent studies have revealed that p53 plays a critical role in negative regulation of the aerobic glycolysis in cancer cells [9,10,11,12]. Under hypoxic conditions cancer cells develop an efficient adaptive www.impactjournals.com/oncotarget metabolic response to ensure their survival and proliferation. It has been well-established that hypoxia can drive the metabolic switch from the oxidative phosphorylation to glycolysis, which is critical for the survival and proliferation of cancer cells in a hypoxic environment [15,16,17]. The results from this study revealed an important role and mechanism for p53 to maintain homeostasis of glucose metabolism under hypoxic conditions, which contributes to p53’s role in tumor suppression
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