Regulation of glycolytic and mitochondrial metabolism by ras

Abstract

High glucose uptake is a characteristic of most metastatic tumors and activation of Ras signaling in immortalized cells increases glycolytic flux into lactate, de novo nucleic acid synthesis and the tricarboxylic acid cycle, and increases NADH shuttling, oxygen consumption and uncoupling of ATP synthase from the proton gradient. Fructose-2,6- bisphosphate, C-Myc, HIF1α and AKT each have been found to be key regulators of glycolysis and to be controlled by Ras signaling, and there is abundant evidence for cross-talk between these regulators. The reprogramming of glycolytic and mitochondrial metabolism by Ras enables an integrated activation of energetic and anabolic pathways via the redox state of NADH that is required for the survival and growth of neoplastic cells in poorly vascularized tumors. Several small molecule antagonists specific for essential metabolic enzymes have been found to be selectively toxic to Ras-transformed cells as opposed to wild-type cells, indicating that this metabolic reprogramming and addiction may have utility for the development of anti-neoplastic agents.