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Complex N-Glycan and Metabolic Control in Tumor Cells

¹ Samuel Lunenfeld Research Institute, Mount Sinai Hospital; Departments of ² Medical Genetics and Microbiology and ³ Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: James W. Dennis, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue R988, Toronto, Ontario, Canada M5G 1X5. Phone: 416-586-4800, ext. 8233; Fax: 416-586-8588; E-mail: Dennis{at}mshri.on.ca.

Golgi ß1,6N-acetylglucosaminyltransferase V (Mgat5) produces ß1,6GlcNAc-branched complex N-glycans on cell surface glycoproteins that bind to galectins and promote surface residency of glycoproteins, including cytokine receptors. Carcinoma cells from polyomavirus middle T (PyMT) transgenic mice on a Mgat5^–/– background have reduced surface levels of epidermal growth factor (EGF) and transforming growth factor-ß (TGF-ß) receptors and are less sensitive to acute stimulation by cytokines in vitro compared with PyMT Mgat5^+/+ tumor cells but are nonetheless tumorigenic when injected into mice. Here, we report that PyMT Mgat5^–/– cells are reduced in size, checkpoint impaired, and following serum withdrawal, fail to down-regulate glucose transport, protein synthesis, reactive oxygen species (ROS), and activation of Akt and extracellular signal-regulated kinase. To further characterize Mgat5^+/+ and Mgat5^–/– tumor cells, a screen of pharmacologically active compounds was done. Mgat5^–/– tumor cells were comparatively hypersensitive to the ROS inducer 2,3-dimethoxy-1,4-naphthoquinone, hyposensitive to tyrosine kinase inhibitors, to Golgi disruption by brefeldin A, and to mitotic arrest by colcemid, hydroxyurea, and camptothecin. Finally, regulation of ROS, glucose uptake, and sensitivities to EGF and TGF-ß were rescued by Mgat5 expression or by hexosamine supplementation to complex N-glycan biosynthesis in Mgat5^–/– cells. Our results suggest that complex N-glycans sensitize tumor cells to growth factors, and Mgat5 is required to balance responsiveness to growth and arrest cues downstream of metabolic flux. [Cancer Res 2007;67(20):9771–80]

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