Aerobic Glycolysis and the Warburg Effect

The Warburg Effect

The Warburg effect is the enhanced conversion of glucose to lactate observed in tumor cells, even in the presence of normal levels of oxygen. Otto Heinrich Warburg demonstrated in 1924 that cancer cells show an increased dependence on glycolysis to meet their energy needs, regardless of whether they were well-oxygenated or not. Converting glucose to lactate, rather than metabolizing it through oxidative phosphorylation in the mitochondria, is far less efficient as less ATP is generated per unit of glucose metabolized. Therefore, a high rate of glucose uptake is required to meet increased energy needs to support rapid tumor progression.

Previously, it was thought the Warburg effect was a consequence of damage to the mitochondria or an adaptation to hypoxic conditions during the early avascular phase of tumor development. Current insight revealed aerobic glycolysis supports various biosynthetic pathways and, consequently, the metabolic requirements for proliferation. The PI3K pathway is considered to be a major determinant of the glycolytic phenotype through AKT1 and mTOR signaling, and subsequent downstream Hypoxy Inducible Factor 1 (HIF-1) transcription factor activation.

Another important pathway is the AMP-activated protein kinase (AMPK) pathway. AMPK is often considered a metabolic checkpoint as it can control cell proliferation when activated under energetic stress, and activation of AMKP results in the inhibition of mTOR activity. Mutations in tumor suppressor genes such as LKB1, involved in AMPK activation, have been identified in certain cancers. Inhibitors of the glycolytic pathway, such as dichloroacetic acid (DCA) and 2-deoxy-d-glucose (2DG) are now being used in clinical studies as potential anticancer agents.