Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nissim Hay Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607 and Research and Development Section, Jesse Brown VA Medical Center, Chicago, Illinois 60612, USA Abstract: Recent years have seen growing interest in cancer metabolism, particularly glucose metabolism in cancer cells. This review summarizes past and recent advances in understanding how cancer cells reprogram glucose metabolism, driven by oncogenic drivers and undifferentiated characteristics. The reprogrammed glucose metabolism in cancer cells is essential for meeting anabolic demands. This review discusses the potential of exploiting this reprogrammed glucose metabolism for therapeutic approaches that selectively target cancer cells. Until two decades ago, cellular glucose metabolism and cancer metabolism were not considered major branches of cancer biology. However, in the past 15 years, there has been growing interest in cancer metabolism, particularly glucose metabolism in cancer cells, which are now integral to cancer biology, similar to signal transduction and transcription. The distinction between cancer cells and normal cells based on accelerated aerobic glycolysis has been exploited for detecting and imaging tumors in vivo. It is surprising that high cellular glucose metabolism has only recently been recognized as one of the hallmarks of cancer. This renewed interest is coupled with the realization that certain oncogenic drivers increase cellular glucose metabolism and general metabolism. One reason for this renewed recognition is the understanding that the PI3K-AKT-mTORC1 signaling pathway, which has an evolutionarily conserved function in metabolism, is frequently activated in cancer cells. Otto Warburg's discovery of high aerobic glycolysis in cancer cells in the late 1920s led him to assume that respiration through oxidative phosphorylation (OXPHO) is impaired in cancer cells. Subsequent debates, notably between Warburg and Sidney Weinhouse, challenged this idea. Weinhouse and colleagues showed that glucose can be oxidized to CO2 in cancer cells, indicating that OXPHO can occur at a rate similar to that in normal cells. Retrospectively, Warburg's data did not support the idea that respiration is diminished in cancer cells. Instead, cancer cells maintain high glucose metabolism and glycolysis despite OXPHO. While most normal cells obey the Crabtree effect, cancer cells do not. They maintain high rates of both glucose metabolism and OXPHO to meet anabolic demands. However, during tumor growth, core cells become hypoxic, leading to decreased OXPHO and increased glycolysis. Glucose metabolism involves not only glycolysis but also other pathways requiring glucose, such as the pentose phosphate pathway (PPP), hexosamine pathway, glycogenesis, serine biosynthesis, and one-carbon metabolism. This review summarizes the mechanisms by which glucose metabolism is reprogrammed in cancer cells and how this reprogramming could be exploited to selectively targetReprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nissim Hay Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607 and Research and Development Section, Jesse Brown VA Medical Center, Chicago, Illinois 60612, USA Abstract: Recent years have seen growing interest in cancer metabolism, particularly glucose metabolism in cancer cells. This review summarizes past and recent advances in understanding how cancer cells reprogram glucose metabolism, driven by oncogenic drivers and undifferentiated characteristics. The reprogrammed glucose metabolism in cancer cells is essential for meeting anabolic demands. This review discusses the potential of exploiting this reprogrammed glucose metabolism for therapeutic approaches that selectively target cancer cells. Until two decades ago, cellular glucose metabolism and cancer metabolism were not considered major branches of cancer biology. However, in the past 15 years, there has been growing interest in cancer metabolism, particularly glucose metabolism in cancer cells, which are now integral to cancer biology, similar to signal transduction and transcription. The distinction between cancer cells and normal cells based on accelerated aerobic glycolysis has been exploited for detecting and imaging tumors in vivo. It is surprising that high cellular glucose metabolism has only recently been recognized as one of the hallmarks of cancer. This renewed interest is coupled with the realization that certain oncogenic drivers increase cellular glucose metabolism and general metabolism. One reason for this renewed recognition is the understanding that the PI3K-AKT-mTORC1 signaling pathway, which has an evolutionarily conserved function in metabolism, is frequently activated in cancer cells. Otto Warburg's discovery of high aerobic glycolysis in cancer cells in the late 1920s led him to assume that respiration through oxidative phosphorylation (OXPHO) is impaired in cancer cells. Subsequent debates, notably between Warburg and Sidney Weinhouse, challenged this idea. Weinhouse and colleagues showed that glucose can be oxidized to CO2 in cancer cells, indicating that OXPHO can occur at a rate similar to that in normal cells. Retrospectively, Warburg's data did not support the idea that respiration is diminished in cancer cells. Instead, cancer cells maintain high glucose metabolism and glycolysis despite OXPHO. While most normal cells obey the Crabtree effect, cancer cells do not. They maintain high rates of both glucose metabolism and OXPHO to meet anabolic demands. However, during tumor growth, core cells become hypoxic, leading to decreased OXPHO and increased glycolysis. Glucose metabolism involves not only glycolysis but also other pathways requiring glucose, such as the pentose phosphate pathway (PPP), hexosamine pathway, glycogenesis, serine biosynthesis, and one-carbon metabolism. This review summarizes the mechanisms by which glucose metabolism is reprogrammed in cancer cells and how this reprogramming could be exploited to selectively target