Fig. 1

Schematic representation of the role of HIF in regulating glycolysis, glutaminolysis and OXPHOS. Variations in the status of oncogenes, tumor suppressor genes and hypoxia, are all important triggers of HIF-1α which drives cancer cells into glycolysis. Activation of HIF-1α increases glucose channeling into glycolysis by activating GLUT transporters and the key metabolic enzymes, lactate dehydrogenase A (LDH-A) and pyruvate dehydrogenase kinase 1 (PDK1). LDH-A drives pyruvate metabolism away from mitochondria, converting it into lactate. PDK1 inhibits mitochondrial pyruvate dehydrogenase (PDH) and therefore prevents pyruvate oxidation in mitochondria. HIF-1α also activates the lactate efflux transporter to remove excess lactate from the cytoplasm, resulting in an increase in extracellular acidification. By decreasing the pH of tumor microenvironment, lactate activates angiogenesis, cell migration and immune suppression pathways, therefore, providing a survival advantage to the tumor cells. Normal cells utilize pyruvate metabolism in mitochondria regulated by tricarboxylic acid (TCA) cycle. The products of TCA cycle, NADH, FADH2 provide electrons for the electron transport chain (ETC) chain. This process is known as oxidative phosphorylation (OXPHOS) and efficiently generates ATP. HIF-1α decreases mitochondrial OXPHOS by activating PDK1, which subsequently inhibits PDH. It also inhibits the excess reactive oxygen species (ROS) produced as a result of inefficient electron transport, therefore, protecting cancer cells against oxidative stress. Under hypoxic conditions and the consequent energy crisis, cancer cells also utilize glutamine to stimulate fatty acid and amino acid biosynthesis for energy production. HIF-2α enhances glutamine uptake which is converted into glutamate and replenishes the TCA cycle. The process of glutaminolysis generates fatty acids and amino acids as an energy source for cancer cells. Glutamate is also utilized for glutathione biosynthesis, which is a major antioxidant and quenches the ROS, therefore providing protection to cancer cells against cytotoxic ROS.