SIRT3 Is a Mitochondrial Tumor Suppressor: A Scientific Tale That Connects Aberrant Cellular ROS, the Warburg Effect, and Carcinogenesis

Tumors exhibit metabolic reprogramming characterized by increased cellular reactive oxygen species (ROS) and the preferential use of glucose, which is known as the Warburg effect. However, the mechanisms by which these processes are linked remain largely elusive. Murine tumors lacking Sirt3 exhibit abnormally high levels of ROS that directly induce genomic instability and increase hypoxia-inducible factor 1 alpha(HIF-1 alpha) protein levels. The subsequent transcription of HIF alpha-dependent target genes results in cellular metabolic reprogramming and increased cellular glucose consumption. In addition, agents that scavenge ROS or reverse the Warburg effect prevent the transformation and malignant phenotype observed in cells lacking Sirt3. Thus, mice lacking Sirt3 provide a model that mechanistically connects aberrant ROS, the Warburg effect, and carcinogenesis. Cancer Res; 72(10); 2468-72. (C) 2012 AACR.