Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review)

Abstract

Metabolic activities in normal cells rely primarily on mitochondrial oxidative phosphorylation (OXPHOS) to generate ATP for energy. Unlike in normal cells, glycolysis is enhanced and OXPHOS capacity is reduced in various cancer cells. It has long been believed that the glycolytic phenotype in cancer is due to a permanent impairment of mitochondrial OXPHOS, as proposed by Otto Warburg. This view is challenged by recent investigations which find that the function of mitochondrial OXPHOS in most cancers is intact. Aerobic glycolysis in many cancers is the combined result of various factors such as oncogenes, tumor suppressors, a hypoxic microenvironment, mtDNA mutations, genetic background and others. Understanding the features and complexity of the cancer energy metabolism will help to develop new approaches in early diagnosis and effectively target therapy of cancer.

Figure 1.

Alterations of oncogene and tumor suppressor and hypoxia drive cancer cells to aerobic glycolysis. The raised levels of HIF1 and c-Myc, and inactivation of p53 are very common in human cancers. HIF1, c-Myc and p53 form the ‘triad’ of transcription factors responsible for the glycolytic phenotype in cancer. HIF1α is induced by hypoxia or activated oncogenes (e.g. Ras, PI3K-Akt and Her) or inactivated tumor suppressors (e.g. p53, pVHL and PTEN) under normoxic conditions. In addition, HIF1 also enhances Myc expression. HIF, hypoxia-inducible factor.

Figure 2.

p53 modulates cell energy metabolism. p53 represses the expression of glucose transporter genes (e.g., GLUT1 and GLUT4) and increases the levels of TIGAR, an inhibitor of glycolysis, in the cytoplasm. In addition, p53 increases the levels of SCO2 in the inner membrane of the mitochondria, consequently promoting mitochondrial respiration. TIGAR, TP53-induced glycolysis and apoptosis regulator; SCO2, synthesis of cytochrome c oxidase 2.