Significance: Metabolic reprogramming is considered to be a critical adaptive biological event that fulfills the energy and biomass demands for cancer cells. One hallmark of metabolic reprogramming is reduced oxidative phosphorylation and enhanced aerobic glycolysis. Such metabolic abnormalities contribute to the accumulation of reactive oxygen species (ROS), the by-products of metabolic pathways. Emerging evidence suggests that ROS can in turn directly or indirectly affect the expression, activity, or subcellular localization of metabolic enzymes, contributing to the moonlighting functions outside of their primary roles. This review summarizes the multifunctions of metabolic enzymes and the involved redox modification patterns, which further reveal the inherent connection between metabolism and cellular redox state. Recent Advances: These noncanonical functions of metabolic enzymes involve the regulation of epigenetic modifications, gene transcription, post-translational modification, cellular antioxidant capacity, and many other fundamental cellular events. The multifunctional properties of metabolic enzymes further expand the metabolic dependencies of cancer cells, and confer cancer cells with a means of adapting to diverse environmental stimuli. Critical Issues: Deciphering the redox-manipulated mechanisms with specific emphasis on the moonlighting function of metabolic enzymes is important for clarifying the pertinence between metabolism and redox processes. Future Directions: Investigation of the redox-regulated moonlighting functions of metabolic enzymes will shed new lights into the mechanism by which metabolic enzymes gain noncanonical functions, and yield new insights into the development of novel therapeutic strategies for cancer treatment by targeting metabolic-redox abnormalities. Antioxid. Redox Signal. 34, 979-1003.
Keywords: cancer therapy; epigenetics; metabolism; moonlighting; redox.