title: Importance of ERK activation in As2O3-induced differentiation and promyelocytic leukemia nuclear bodies formation in neuroblastoma cells.
abstract: Neuroblastoma malignant cell growth is dependent on their undifferentiated status. Arsenic trioxide (As2O3) induces neuroblastoma cell differentiation in vitro, but its mechanisms still remains unknown. We used three human neuroblastoma cell lines (SH-SY5Y, IGR-N-91, LAN-1) that differ from their MYCN and p53 status to explore the intracellular events activated by As2O3 and involved in neurite outgrowth, a morphological marker of differentiation. As2O3 (2μM) induced neurite outgrowth in all cell lines, which was dependent on ERK activation but independent on MYCN status. This process was induced either by a sustained (3 days) or a transient (2h) incubation with As2O3, indicating that very early events trigger the induction of differentiation. In parallel, As2O3 induced a rapid assembly of promyelocytic leukemia nuclear bodies (PML-NB) in an ERK-dependent manner. In conclusion, mechanisms leading to neuroblastoma cell differentiation in response to As2O3 appear to involve the ERK pathway activation and PML-NB formation, which are observed in response to other differentiating molecules such as retinoic acid derivates. This open new perspectives based on the use of treatment combinations to potentiate the differentiating effects of each drug alone and reduce their adverse side effects.
authors.affiliation: Laboratoire MERCI EA3829, Université de Rouen, Faculté de Médecine-Pharmacie, 22 Boulevard Gambetta, 76183 Rouen, France. Electronic address: alexandre.petit@etu.univ-rouen.fr.
authors.forename: A
authors.initials: A
authors.lastname: Petit
authors.forename: A
authors.initials: A
authors.lastname: Delaune
authors.forename: A
authors.initials: A
authors.lastname: Falluel-Morel
authors.forename: J-P
authors.initials: JP
authors.lastname: Goullé
authors.forename: J-P
authors.initials: JP
authors.lastname: Vannier
authors.forename: I
authors.initials: I
authors.lastname: Dubus
authors.forename: M
authors.initials: M
authors.lastname: Vasse
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000187:drug effects / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D000071447:N-Myc Proto-Oncogene Protein; D016501:Neurites / Q000187:drug effects / Q000648:ultrastructure; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D000077237:Arsenic Trioxide
keywords: Arsenic trioxide; Differentiation; ERK pathway; Neuroblastoma; PML-NB