O-GlcNAc signaling: a metabolic link between diabetes and cancer?

Abstract

O-linked β-N-acetylglucosamine (O-GlcNAc) is a sugar attachment to serine or threonine hydroxyl moieties on nuclear and cytoplasmic proteins. In many ways, O-GlcNAcylation is similar to phosphorylation since both post-translational modifications cycle rapidly in response to internal or environmental cues. O-GlcNAcylated proteins are involved in transcription, translation, cytoskeletal assembly, signal transduction, and many other cellular functions. O-GlcNAc signaling is intertwined with cellular metabolism; indeed, the donor sugar for O-GlcNAcylation (UDP-GlcNAc) is synthesized from glucose, glutamine, and UTP via the hexosamine biosynthetic pathway. Emerging research indicates that O-GlcNAc signaling and its crosstalk with phosphorylation are altered in metabolic diseases, such as diabetes and cancer. O-GlcNAc: A metabolic Signaling MoleculeOne of the most pressing medical issues facing industrialized countries is the rapid rise of type 2 diabetes, a metabolic disorder characterized by severely elevated blood glucose and insensitivity to insulin. In the United States alone, 7.8% of the population is diagnosed with diabetes, and up to 57 million Americans have pre-diabetes. The cost for treating type 2 diabetes was $174 billion in 2007, and consumed 32% of Medicare spending (http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf). Furthermore, diabetes is a risk factor for Alzheimer's disease, cardiovascular disease, and cancer, but the underlying mechanisms remain poorly understood 1 . Both diabetes and cancer show cellular alterations in energy metabolism, stress responsiveness, and signaling. Multiple biochemical processes are involved; however, one potential link in all of these diseases is disrupted O-GlcNAc signaling.O-GlcNAc is a post-translational protein modification consisting of a single Nacetylglucosamine moiety attached via an O-β-glycosidic linkage to serine and threonine residues2 -4. O-GlcNAc modified proteins are generally either cytoplasmic or nuclear proteins, and unlike asparagine-linked or mucin-type O-glycosylation, O-GlcNAc is not further processed into a complex oligosaccharide2 , 3. In many ways, O-GlcNAc is similar to protein phosphorylation; for example the sugar can be attached or removed dynamically in response to changes in the cellular environment triggered by stress, hormones, or nutrients [5,6]. Because O-GlcNAc is attached to serine/threonine residues, the sugar is in direct competition with phosphorylation (eg. c-myc7). Furthermore, O-GlcNAcylated or phosphorylated residues can be in close proximity to each other and sterically impair the attachment of the other © 2010 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production proce...

Energy Management by Enhanced Glycolysis in G1-phase in Human Colon Cancer Cells In Vitro and In Vivo

“…In fact, the significant increase in concentrations of ATP and UTP in G 1 phase was greater than in S and G 2 -M phases in vivo. As UDP-GlcNAc levels are elevated in parallel with glucose use (38), the current observation showing the higher level of UDP-GlcNAc in G 1 phase in vivo suggests a possible accelerated glucose uptake in the phase. When the concentrations of metabolites were compared between in vitro and in vivo, there were some discrepancy, i.e., cellular amounts of GSH were greater in G 1 than in G 2 -M phase in vitro, whereas they did not statistically differ in vivo.…”

A Putative Polypeptide N-Acetylgalactosaminyltransferase/Williams-Beuren Syndrome Chromosome Region 17 (WBSCR17) Regulates Lamellipodium Formation and Macropinocytosis

“…Our study suggests that the mucin-type O-glycans generated by WBSCR17 also regulate the glycoprotein incorporation through macropinocytosis in response to the GlcNAc concentration in the cell. Because UDP-GlcNAc, which is convertible to UDP-GalNAc by an epimerase, can be metabolically produced from nutrients other than GlcNAc, such as glucose, amino acids, fatty acids, and nucleic acids (37,38), WBSCR17 may work as a modulator of macropinocytosis in the cells in a nutrition concentration-dependent manner; excess nutrition enhances the expression of WBSCR17, giving rise to the reduced macropinocytosis, whereas nutrition shortage, in turn, reduces WBSCR17 and promotes macropinocytosis to take up the nutrients from the environmental solutes (Fig. 10E).…”

Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma

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