title: T11TS inhibits Angiopoietin-1/Tie-2 signaling, EGFR activation and Raf/MEK/ERK pathway in brain endothelial cells restraining angiogenesis in glioma model.
abstract: Malignant gliomas represent one of the most aggressive and hypervascular primary brain tumors. Angiopoietin-1, the peptide growth factor activates endothelial Tie-2 receptor promoting vessel maturation and vascular stabilization steps of angiogenesis in glioma. Epidermal growth factor receptor (EGFR) and Tie-2 receptor on endothelial cells once activated transmits signals through downstream Raf/MEK/ERK pathway promoting endothelial cell proliferation and migration which are essential for angiogenesis induction. The in vivo effect of sheep erythrocyte membrane glycopeptide T11-target structure (T11TS) on angiopoietin-1/Tie-2 axis, EGFR signaling and Raf/MEK/ERK pathway in glioma associated endothelial cells has not been investigated previously. The present study performed with rodent glioma model aims to investigate the effect of T11TS treatment on angiopoietin-1/Tie-2 signaling, EGFR activity and Raf/MEK/ERK pathway in glioma associated endothelial cells within glioma milieu. T11TS administration in rodent glioma model inhibited angiopoietin-1 expression and attenuated Tie-2 expression and activation in glioma associated brain endothelial cells. T11TS treatment also downregulated total and phosphorylated EGFR expression in glioma associated endothelial cells. Additionally T11TS treatment inhibited Raf-1 expression, MEK-1 and ERK-1/2 expression and phosphorylation in glioma associated brain endothelial cells. Thus T11TS therapy remarkably inhibits endothelial angiopoietin-1/Tie-2 signaling associated with vessel maturation and simultaneously antagonizes endothelial cell proliferation signaling by blocking EGFR activation and components of Raf/MEK/ERK pathway. Collectively, the findings demonstrate a multi-targeted anti-angiogenic activity of T11TS which augments the potential for clinical translation of T11TS as an effective angiogenesis inhibitor for glioma treatment.
authors: Cellular and Molecular Immunology Laboratory, Department of Laboratory Medicine, School of Tropical Medicine, 108 C. R. Avenue, Kolkata 700073, West Bengal, India.
authors: Debanjan
authors: D
authors: Bhattacharya
authors: Cellular and Molecular Immunology Laboratory, Department of Laboratory Medicine, School of Tropical Medicine, 108 C. R. Avenue, Kolkata 700073, West Bengal, India.
authors: Suhnrita
authors: S
authors: Chaudhuri
authors: Cellular and Molecular Immunology Laboratory, Department of Laboratory Medicine, School of Tropical Medicine, 108 C. R. Avenue, Kolkata 700073, West Bengal, India.
authors: Manoj Kumar
authors: MK
authors: Singh
authors: Cellular and Molecular Immunology Laboratory, Department of Laboratory Medicine, School of Tropical Medicine, 108 C. R. Avenue, Kolkata 700073, West Bengal, India. Electronic address: swapna.chaudhuri@gmail.com.
authors: Swapna
authors: S
authors: Chaudhuri
mesh_terms: D042683:Angiopoietin-1 / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D018801:CD2 Antigens / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats; D042787:Receptor, TIE-2 / Q000378:metabolism*; D012756:Sheep
chemical_list: D042683:Angiopoietin-1; D018801:CD2 Antigens; D066246:ErbB Receptors; D042787:Receptor, TIE-2; D019908:Proto-Oncogene Proteins c-raf; C546782:Raf1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; D048369:MAP Kinase Kinase 1
keywords: Angiopoietin-1; EGFR; Glioma; Raf/MEK/ERK pathway; T11TS; Tie-2 signaling