title: Inhibition of the Jagged/Notch pathway inhibits retinoblastoma cell proliferation via suppressing the PI3K/Akt, Src, p38MAPK and Wnt/β‑catenin signaling pathways.
abstract: The Notch signaling pathway is a highly conserved developmental pathway, which is important in the regulation of cellular proliferation, differentiation and apoptosis. The aberrant expression of the Notch pathway has been associated with carcinogenesis in various types of cancer. In order to investigate the expression profiles and biological functions of Notch receptors and ligands in retinoblastoma, the expression levels of their proteins in the human retinoblastoma cell line SO‑Rb50 using western blot analysis was assessed. The present study revealed that Notch1 and Jagged2 were highly expressed compared with human retinal pigment epithelial cells. When treated with DAPT, a specific inhibitor of Notch receptor cleavage, expression of Notch1 and Jagged2 were downregulated in a dose‑dependent manner, which was accompanied by substantial cell growth arrest, as indicated by the Cell Counting kit‑8 assay. In addition, phosphorylation of Akt, p38 mitogen‑activated protein kinase and Src, together with the expression of phosphoinositide 3‑kinase and β‑catenin, was abated in a dose‑dependent manner. However, expression of either total extracellular signal‑regulated kinase (Erk)1/2 or phospho‑Erk1/2 was not changed in SO‑Rb50 cells. These findings demonstrated that the Jagged2/Notch1 pathway can promote oncogenesis in retinoblastoma in co‑operation with multiple signaling pathways. The inhibition of the Notch signaling pathway by DAPT represents a potentially attractive strategy for the therapy of retinoblastoma.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510060, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510060, P.R. China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat‑sen University, Guangzhou, Guangdong 510060, P.R. China.
authors.forename: Mingguang
authors.initials: M
authors.lastname: He
mesh_terms: D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019572:Retinal Neoplasms / Q000378:metabolism / Q000473:pathology; D012175:Retinoblastoma / Q000378:metabolism / Q000473:pathology; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D004151:Dipeptides; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases