Complex N-glycan and metabolic control in tumor cells.

Mendelsohn R, Cheung P, Berger L, Partridge E, Lau K, Datti A, Pawling J, Dennis JW
Cancer Res. 2007 67 (20): 9771-80

PMID: 17942907 · DOI:10.1158/0008-5472.CAN-06-4580

Golgi beta1,6N-acetylglucosaminyltransferase V (Mgat5) produces beta1,6GlcNAc-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-beta (TGF-beta) 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-beta 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.

MeSH Terms (17)

Animals Antigens, Polyomavirus Transforming Cell Growth Processes Cell Line, Tumor Glucose Golgi Apparatus Mammary Neoplasms, Experimental MAP Kinase Signaling System Mice Mice, Transgenic Mitochondria Mitogen-Activated Protein Kinase Kinases N-Acetylglucosaminyltransferases Polysaccharides Proto-Oncogene Proteins c-akt Reactive Oxygen Species Uridine Diphosphate N-Acetylglucosamine

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