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Abstract Yeast and cancer cells are metabolically similar as they use fermentation of glucose as a primary means of generating energy. Reliance on glucose fermentation makes both of these cell types highly sensitive to the toxic glucose analog, 2-deoxyglucose. Here we review the cellular and metabolic pathways that play a role in 2-deoxyglucose sensitivity and discuss how the modi- fications to these pathways result in acquisition of 2-deoxyglucose resistance. Insights gained from genetic and proteomic studies in yeast provide new ideas for the design of combinatorial therapies for cancer treatment.

Model for 2DG uptake and signaling. 2DG is taken up by yeast cells by hexose transporter (HXT) proteins and phosphorylated to 2DG-6P by hexokinase enzymes. Accumulation of 2DG-6P is toxic to cells. Cellular adaptation to the presence of 2DG requires the Snf1/AMPK kinase complex. Resistance to 2DG can be imparted by activation of Snf1 kinase signaling via dominant alleles in the genes encoding the kinase subunits or by loss-of-function alleles in the genes (GLC7 and REG1) encoding the PP1 phosphatase that down-regulates Snf1. Adaptation to 2DG is also promoted by mutations in the hexokinase 2 gene (HXK2) or up-regulation of the DOG1 and DOG2 phosphatases, which reduce production or enhance the degradation of the toxic 2DG-6P, respectively. Nearly all mutations that confer 2DG resistance increase HXT retention at the cell surface, which is controlled in a Snf1- and α-arrestin-dependent manner in response to 2DG. While Snf1 regulation of Mig1 (not show) alleviates repression of some genes in response to 2DG, other transcriptional responses to 2DG likely to occur via Snf1-independent signaling pathways.