title: Targeting GD2 ganglioside and aurora A kinase as a dual strategy leading to cell death in cultures of human neuroblastoma cells.
abstract: The mechanism of the inhibitory effect of anti-GD2 ganglioside (GD2) 14G2a mouse monoclonal antibody (mAb) on human neuroblastoma cells survival was studied in vitro. It was recently shown in IMR-32 cells that death induced by this antibody exhibited several characteristics typical of apoptosis. In this study we used cytotoxixity assays, qRT-PCR and immunoblotting to evaluate the response of several human neuroblastoma cell lines to the anti-GD2 14G2a mAb. We showed that the mAb decreases all three aurora kinases expression and phosphorylation in IMR-32 and LA-N-1 cells. Most importantly, we show, that MK-5108 specific aurora A kinase inhibitor decreases neuroblastoma cell survival, and when used in combination with the mAb, significantly potentiates cytotoxicity against IMR-32, CHP-134, and LA-N-5 neuroblastoma cells in vitro. It was shown that downregulation of aurora A kinase by the therapeutic antibody is associated with decreased levels of MYCN protein in cytoplasm, and induced expression of PHLDA1 and P53 proteins.
authors: Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 7, Gronostajowa St., 30-387 Kraków, Poland.
authors: Irena
authors: I
authors: Horwacik
authors: Małgorzata
authors: M
authors: Durbas
authors: Elżbieta
authors: E
authors: Boratyn
authors: Paulina
authors: P
authors: Węgrzyn
authors: Hanna
authors: H
authors: Rokita
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D005434:Flow Cytometry; D005732:Gangliosides / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C547876:4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin to 2-yl)methyl) cyclohexanecarboxylic acid; D000911:Antibodies, Monoclonal; D003509:Cyclohexanecarboxylic Acids; D005732:Gangliosides; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C491923:PHLDA1 protein, human; D047428:Protein Kinase Inhibitors; C495901:TP53 protein, human; D013844:Thiazoles; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C019403:ganglioside, GD2; D064096:Aurora Kinase A; D053148:Caspase 3; D053179:Caspase 7
keywords: Aurora kinases; GD2 ganglioside; Monoclonal antibody; Neuroblastoma; P53