(680.4) N-Glycosylation Inhibitor Interferes with WNT Signaling and Inhibits Angiogenesis

Poster Board Number: A479

Dipak Banerjee (University of Puerto Rico, University of Puerto Rico), Arelis Lebron (University of Puerto Rico), Diego Collazo Irizarry (University of Puerto Rico), Krishna Baksi (Universidad Central del Caribe)

Neovascularization, a normal physiological process orchestrates through vasculogenesis from mesoderm cell precursors.  In healthy adults, the vasculature is quiescent but pathological angiogenesis is evident during wound healing and in tumor growth.  Thus, angiogenesis becomes a fundamental step for tumors transitioning from a benign state to malignancy where endothelial cells proliferate 45 times faster.   Our laboratory has recently shown that asparagine-linked (N-linked) protein glycosylation is essential for enhanced capillary endothelial cell proliferation in situ.  Inhibiting N-glycosylation with Tunicamycin causes G1 arrest and induces cell death by apoptosis due to “ER stress" and is not reversible by VEGF.  Tunicamycin also inhibits angiogenesis in vivo in Matrigel™ implants in nude mice as well as in a pre-clinical mouse model of double negative (ER-/PR-/HER2+) breast tumor.  

Wnt pathway is involved in cellular differentiation to organogenesis, and supports angiogenesis.  In “canonical” Wnt/β-catenin signaling pathway β-catenin translocates to nucleus and activates Wnt/β-catenin target genes, including vascular endothelial growth factor A (VEGF-A).  Irrespective of the Wnt ligand and Frizzled being glycoproteins, the cross-talk between protein N-glycosylation and the Wnt pathway has not been addressed. This led us to hypothesize that decreased expression of Wnt protein(s) in Tunicamycin treated endothelial cell would decrease cellular proliferation.   We have used capillary endothelial cells as a model and observed down regulated expression of Wnt proteins in Tunicamycin treated cells. Our results support Tunicamycin-induced "ER stress" interferes with Wnt signaling and inhibits angiogenesis. We, therefore, conclude molecular understanding of the process would provide a novel target to inhibit angiogenesis and breast tumor progression.

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