The Glycogen Shunt Maintains Glycolytic Homeostasis and the Warburg Effect in Cancer

Under aerobic conditions cancer cells consume more glucose than they oxidize for energy, a phenomenon known as the Warburg effect. There have been many proposed critical functions for the Warburg effect in cancer cells, but none have been definitively shown. The glycogen shunt has been recently shown to be essential for cancer cell survival. The critical role of the glycogen shunt in maintaining metabolic homeostasis, recently shown in yeast, provides a novel explanation and mechanism for its importance in cancer cells and the Warburg effect. Despite many decades of study there is a lack of a quantitative explanation for the Warburg effect in cancer. We propose that the glycogen shunt, a pathway recently shown to be critical for cancer cell survival, may explain the excess lactate generation under aerobic conditions characteristic of the Warburg effect. The proposal is based on research on yeast and mammalian muscle and brain that demonstrates that the glycogen shunt functions to maintain homeostasis of glycolytic intermediates and ATP during large shifts in glucose supply or demand. Loss of the glycogen shunt leads to cell death under substrate stress. Similarities between the glycogen shunt in yeast and cancer cells lead us here to propose a parallel explanation of the lactate produced by cancer cells in the Warburg effect. The model also explains the need for the active tetramer and inactive dimer forms of pyruvate kinase (PKM2) in cancer cells, similar to the two forms of Pyk2p in yeast, as critical for regulating the glycogen shunt flux. The novel role proposed for the glycogen shunt implicates the high activities of glycogen synthase and fructose bisphosphatase in tumors as potential targets for therapy. Despite many decades of study there is a lack of a quantitative explanation for the Warburg effect in cancer. We propose that the glycogen shunt, a pathway recently shown to be critical for cancer cell survival, may explain the excess lactate generation under aerobic conditions characteristic of the Warburg effect. The proposal is based on research on yeast and mammalian muscle and brain that demonstrates that the glycogen shunt functions to maintain homeostasis of glycolytic intermediates and ATP during large shifts in glucose supply or demand. Loss of the glycogen shunt leads to cell death under substrate stress. Similarities between the glycogen shunt in yeast and cancer cells lead us here to propose a parallel explanation of the lactate produced by cancer cells in the Warburg effect. The model also explains the need for the active tetramer and inactive dimer forms of pyruvate kinase (PKM2) in cancer cells, similar to the two forms of Pyk2p in yeast, as critical for regulating the glycogen shunt flux. The novel role proposed for the glycogen shunt implicates the high activities of glycogen synthase and fructose bisphosphatase in tumors as potential targets for therapy. the main molecule providing energy to drive enzymatic reactions in the cell. a glucose polysaccharide that is the major storage compound for glucose in mammals. the coordinated pathways of glycogen storage, breakdown, and glycolysis to maintain homeostasis of metabolic intermediates and proper timing of glucose utilization. It differs from previous metabolic descriptions that treated the pathways (glycogen synthesis, breakdown, and glycolysis) as separately regulated. phosphorylated metabolites such as G6P that are produced by the glycolytic metabolism of glucose. an enzyme in the glycolytic pathway that in cancer cells is largely inactive, despite the enhanced need for aerobic glycolysis. Its regulatory role in the glycogen shunt may explain the importance of the inactive form. under aerobic conditions cancer cells consume more glucose than they oxidize for energy, a phenomenon named the Warburg effect by Racker in the 1970s. It is also often referred to as aerobic glycolysis.