Deregulated cellular metabolism is a hallmark of tumors. Cancer cells increase glucose and glutamine flux to provide energy needs and macromolecular synthesis demands. Several studies have been focused on the importance of glycolysis and pentose phosphate pathway. However, a neglected but very important branch of glucose metabolism is the hexosamine biosynthesis pathway (HBP). The HBP is a branch of the glucose metabolic pathway that consumes ϳ2-5% of the total glucose, generating UDP-GlcNAc as the end product. UDP-GlcNAc is the donor substrate used in multiple glycosylation reactions. Thus, HBP links the altered metabolism with aberrant glycosylation providing a mechanism for cancer cells to sense and respond to microenvironment changes. Here, we investigate the changes of glucose metabolism during epithelial mesenchymal transition (EMT) and the role of O-GlcNAcylation in this process. We show that A549 cells increase glucose uptake during EMT, but instead of increasing the glycolysis and pentose phosphate pathway, the glucose is shunted through the HBP. The activation of HBP induces an aberrant cell surface glycosylation and O-GlcNAcylation. The cell surface glycans display an increase of sialylation ␣2-6, poly-LacNAc, and fucosylation, all known epitopes found in different tumor models. In addition, modulation of O-GlcNAc levels was demonstrated to be important during the EMT process. Taken together, our results indicate that EMT is an applicable model to study metabolic and glycophenotype changes during carcinogenesis, suggesting that cell glycosylation senses metabolic changes and modulates cell plasticity.Altered metabolism represents the first known difference between cancer cells and normal cells (1). The Warburg effect consists of an increase of glucose uptake for producing energy by a high rate of glycolysis followed by lactic acid fermentation even under high oxygen tension ("aerobic glycolysis"). Understanding the metabolism of tumors remains a topic of intense study with important therapeutic potential (2, 3). Several advances in cancer metabolism research over past years have enhanced our understanding of how aerobic glycolysis and other metabolic shifts support the anabolic demands of high growth rate (4). Traditionally, the study of glucose metabolism usually focused on the use of glucose for energy needs. However, cancer cells use glucose in anabolic pathways that provide precursors for the synthesis of lipids, proteins, glycans, and DNA to satisfy the demands of growth and proliferation. Several studies have been focused on the importance of the pentose phosphate pathway (PPP), 3 to generate NADPH that ensures the antioxidant defenses of the cell and to generate the nucleotides in high demand or the use of intermediates of the glycolytic pathway to generate molecules such as lipids or amino acids (5). However, a neglected but integral branch of glucose metabolism is the hexosamine biosynthesis pathway (HBP).Approximately 2-5% of glucose influx is directed to the HBP by the rate-limiting enzyme ...

Hyperglycemia is a common feature of diabetes mellitus, considered as a risk factor for cancer. However, its direct effects in cancer cell behavior are relatively unexplored. Herein we show that high glucose concentration induces aberrant glycosylation, increased cell proliferation, invasion and tumor progression of colon cancer. By modulating the activity of the rate-limiting enzyme, glutamine-fructose-6-phosphate amidotransferase (GFAT), we demonstrate that hexosamine biosynthetic pathway (HBP) is involved in those processes. Biopsies from patients with colon carcinoma show increased levels of GFAT and consequently aberrant glycans’ expression suggesting an increase of HBP flow in human colon cancer. All together, our results open the possibility that HBP links hyperglycemia, aberrant glycosylation and tumor malignancy, and suggest this pathway as a potential therapeutic target for colorectal cancer.

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