N-Glycans in cancer progression

• Published in: Glycobiology (Oxford) Vol. 18; no. 10; pp. 750 - 760
• Main Authors: Lau, Ken S, Dennis, James W
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.10.2008; Oxford Publishing Limited (England)
• Subjects: Animals; cancer; cytokine signaling; Disease Progression; Humans; metabolism; N-Acetylglucosaminyltransferases - metabolism; N-glycans; Neoplasms - metabolism; Neoplasms - pathology; Polysaccharides - metabolism; Protein Binding; Signal Transduction; cytokine signaling; cancer; metabolism; glycans
• ISSN: 0959-6658; 1460-2423
• DOI: 10.1093/glycob/cwn071

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.