title: Unfolded protein response is required in nu/nu mice microvasculature for treating breast tumor with tunicamycin.
abstract: Up-regulation of the dolichol pathway, a "hallmark" of asparagine-linked protein glycosylation, enhances angiogenesis in vitro. The dynamic relationship between these two processes is now evaluated with tunicamycin. Capillary endothelial cells treated with tunicamycin were growth inhibited and could not be reversed with exogenous VEGF(165). Inhibition of angiogenesis is supported by down-regulation of (i) phosphorylated VEGFR1 and VEGFR2 receptors; (ii) VEGF(165)-specific phosphotyrosine kinase activity; and (iii) Matrigel(TM) invasion and chemotaxis. In vivo, tunicamycin prevented the vessel development in Matrigel(TM) implants in athymic Balb/c (nu/nu) mice. Immunohistochemical analysis of CD34 (p < 0.001) and CD144 (p < 0.001) exhibited reduced vascularization. A 3.8-fold increased expression of TSP-1, an endogenous angiogenesis inhibitor in Matrigel(TM) implants correlated with that in tunicamycin (32 h)-treated capillary endothelial cells. Intravenous injection of tunicamycin (0.5 mg/kg to 1.0 mg/kg) per week slowed down a double negative (MDA-MB-435) grade III breast adenocarcinoma growth by ∼50-60% in 3 weeks. Histopathological analysis of the paraffin sections indicated significant reduction in vessel size, the microvascular density and tumor mitotic index. Ki-67 and VEGF expression in tumor tissue were also reduced. A significant reduction of N-glycan expression in tumor microvessel was also observed. High expression of GRP-78 in CD144-positive cells supported unfolded protein response-mediated ER stress in tumor microvasculature. ∼65% reduction of a triple negative (MDA-MB-231) breast tumor xenograft in 1 week with tunicamycin (0.25 mg/kg) given orally and the absence of systemic and/or organ failure strongly supported tunicamycin's potential for a powerful glycotherapeutic treatment of breast cancer in the clinic.
authors.affiliation: Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico 00936-5067.
authors.forename: Aditi
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Jing-Yu
authors.initials: JY
authors.lastname: Lang
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030,; Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan 404.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Cancer Research Unit, Veterans Affairs Medical Center and Division of Hematology and Oncology, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160-7350.
authors.forename: Krishanu
authors.initials: K
authors.lastname: Sengupta
authors.affiliation: Cancer Research Unit, Veterans Affairs Medical Center and Division of Hematology and Oncology, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160-7350.
authors.forename: Sushanta K
authors.initials: SK
authors.lastname: Banerjee
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, Universidad Central del Caribe, Bayamon, Puerto Rico 00960-3001, and.
authors.forename: Krishna
authors.initials: K
authors.lastname: Baksi
authors.affiliation: Department of Biochemistry, School of Medicine, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico 00936-5067,; Institute of Functional Nanomaterials, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico 00931-1907. Electronic address: dipak.banerjee@upr.edu.
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Banerjee
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019700:Thrombospondin 1 / Q000096:biosynthesis; D014183:Transplantation, Heterologous; D014415:Tunicamycin / Q000494:pharmacology*; D056811:Unfolded Protein Response / Q000187:drug effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000998:Antiviral Agents; D019700:Thrombospondin 1; D014415:Tunicamycin; D040301:Vascular Endothelial Growth Factor Receptor-2