Aldo Keto Reductases AKR1B1 and AKR1B10 in Cancer: Molecular Mechanisms and Signaling Networks

Deregulation of metabolic pathways has increasingly been appreciated as a major driver of cancer in recent years. The principal cancer-associated alterations in metabolism include abnormal uptake of glucose and amino acids and the preferential use of metabolic pathways for the production of biomass and nicotinamide adenine dinucleotide phosphate (NADPH). Aldo-keto reductases (AKRs) are NADPH dependent cytosolic enzymes that can catalyze the reduction of carbonyl groups to primary and secondary alcohols using electrons from NADPH. Aldose reductase, also known as AKR1B1, catalyzes the conversion of excess glucose to sorbitol and has been studied extensively for its role in a number of diabetic pathologies. In recent years, however, high expression of the AKR1B and AKR1C family of enzymes has been strongly associated with worse outcomes in different cancer types. This review provides an overview of the catalysis-dependent and independent data emerging on the molecular mechanisms of the functions of AKRBs in different tumor models with an emphasis of the role of these enzymes in chemoresistance, inflammation, oxidative stress and epithelial-to-mesenchymal transition.