Glycobiology Advance Access originally published online on August 13, 2008
Glycobiology 2008 18(10):750-760; doi:10.1093/glycob/cwn071
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N-Glycans in cancer progression
2 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
3 Department of Biochemistry
4 Department of Molecular Genetics, Laboratory Medicine and Pathology, University of Toronto, ON, Canada
1 To whom correspondence should be addressed: Tel: +1-416-586-8233; Fax: +1-416-586-8587; e-mail: dennis{at}mshri.on.ca
Received on May 5, 2008; revised on July 21, 2008; accepted on July 27, 2008
N-Glycan branching in the medial-Golgi generates ligands for lattice-forming lectins (e.g., galectins) that regulate surface levels of glycoproteins including epidermal growth factor (EGF) and transforming growth factor-β (TGF-β) receptors. Moreover, functional classes of glycoproteins differ in N-glycan multiplicities (number of N-glycans/peptide), a genetically encoded feature of glycoproteins that interacts with metabolic flux (UDP-GlcNAc) and N-glycan branching to differentially regulate surface levels. Oncogenesis increases β1,6-N-acetylglucosaminyltransferase V (encoded by Mgat5) expression, and its high-affinity galectin ligands promote surface retention of growth receptors with a reduced dependence on UDP-GlcNAc. Mgat5–/– tumor cells are less metastatic in vivo and less responsive to cytokines in vitro, but undergo secondary changes that support tumor cell proliferation. These include loss of Caveolin-1, a negative regulator of EGF signaling, and increased reactive oxygen species, an inhibitor of phosphotyrosine phosphatases. These studies suggest a systems approach to cancer treatment where the surface distribution of receptors is targeted through metabolism and N-glycan branching to induce growth arrest.
Key words: cancer / cytokine signaling / metabolism / N-glycans
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