title: Galectin-3 impairment of MYCN-dependent apoptosis-sensitive phenotype is antagonized by nutlin-3 in neuroblastoma cells.
abstract: MYCN amplification occurs in about 20-25% of human neuroblastomas and characterizes the majority of the high-risk cases, which display less than 50% prolonged survival rate despite intense multimodal treatment. Somehow paradoxically, MYCN also sensitizes neuroblastoma cells to apoptosis, understanding the molecular mechanisms of which might be relevant for the therapy of MYCN amplified neuroblastoma. We recently reported that the apoptosis-sensitive phenotype induced by MYCN is linked to stabilization of p53 and its proapoptotic kinase HIPK2. In MYCN primed neuroblastoma cells, further activation of both HIPK2 and p53 by Nutlin-3 leads to massive apoptosis in vitro and to tumor shrinkage and impairment of metastasis in xenograft models. Here we report that Galectin-3 impairs MYCN-primed and HIPK2-p53-dependent apoptosis in neuroblastoma cells. Galectin-3 is broadly expressed in human neuroblastoma cell lines and tumors and is repressed by MYCN to induce the apoptosis-sensitive phenotype. Despite its reduced levels, Galectin-3 can still exert residual antiapoptotic effects in MYCN amplified neuroblastoma cells, possibly due to its specific subcellular localization. Importantly, Nutlin-3 represses Galectin-3 expression, and this is required for its potent cell killing effect on MYCN amplified cell lines. Our data further characterize the apoptosis-sensitive phenotype induced by MYCN, expand our understanding of the activity of MDM2-p53 antagonists and highlight Galectin-3 as a potential biomarker for the tailored p53 reactivation therapy in patients with high-risk neuroblastomas.
authors.affiliation: Department of Experimental Medicine, Sapienza University, Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Veschi
authors.forename: Marialaura
authors.initials: M
authors.lastname: Petroni
authors.forename: Beatrice
authors.initials: B
authors.lastname: Cardinali
authors.forename: Carlo
authors.initials: C
authors.lastname: Dominici
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.forename: Luigi
authors.initials: L
authors.lastname: Frati
authors.forename: Armando
authors.initials: A
authors.lastname: Bartolazzi
authors.forename: Alberto
authors.initials: A
authors.lastname: Gulino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
mesh_terms: D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects; D004249:DNA Damage; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D005784:Gene Amplification; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008954:Models, Biological; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D037502:Galectin 3; D007093:Imidazoles; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases