Oxidative phosphorylation and cancer: The ongoing warburg hypothesis

Abstract

More than eight decades ago, the German physiologist Otto Warburg observed that cancer cells in the presence of oxygen produced large amounts of lactate and proposed that impaired oxidative metabolism may cause cancer. This formulation, later known as the Warburg hypothesis, was investigated and debated for several decades. The development of molecular biology and the discovery of oncogenes and tumor suppressor genes in subsequent years shifted the general interest in the cancer field into directions other than metabolism and promoted the abandoning of the Warburg hypothesis or its consideration as an epiphenomenon of cell transformation. In recent years, a renaissance in the field of mitochondria has occurred in biological studies. This has happened mostly by the recognition of the key functional role that this organelle plays in the execution of cell death and, thus, for its participation in the development of a vast array of human pathologies. The cancer field was not indifferent to these changes, and the Warburg hypothesis was brought back to the scene with renewed strength. Specifically, recent findings suggest that cancer is associated with a decrease in the activity and expression of β-F1-ATPase, a key subunit of the mitochondrial ATP synthase. This alteration has been shown to limit oxidative phosphorylation and to trigger the induction of glycolysis to provide energy to the cell thus configuring the earlier Warburg observation in an additional hallmark of the cancer cell. Moreover, increased and decreased cellular mitochondrial activities are respectively associated with suppression and development of cancer. We suggest that reactivating mitochondrial metabolism by pharmacologic or dietary measures and/or tackling the deviant glycolysis in cancer cells may efficiently suppress malignant growth. © Humana Press, a part of Springer Science+Business Media, LLC 2009.