title: S(+)-ibuprofen destabilizes MYC/MYCN and AKT, increases p53 expression, and induces unfolded protein response and favorable phenotype in neuroblastoma cell lines.
abstract: Neuroblastoma is a common pediatric solid tumor that exhibits a striking clinical bipolarity: favorable and unfavorable. The survival rate of children with unfavorable neuroblastoma remains low among all childhood cancers. MYCN and MYC play a crucial role in determining the malignancy of unfavorable neuroblastomas, whereas high-level expression of the favorable neuroblastoma genes is associated with a good disease outcome and confers growth suppression of neuroblastoma cells. A small fraction of neuroblastomas harbors TP53 mutations at diagnosis, but a higher proportion of the relapse cases acquire TP53 mutations. In this study, we investigated the effect of S(+)-ibuprofen on neuroblastoma cell lines, focusing on the expression of the MYCN, MYC, AKT, p53 proteins and the favorable neuroblastoma genes in vitro as biomarkers of malignancy. Treatment of neuroblastoma cell lines with S(+)-ibuprofen resulted in a significant growth suppression. This growth effect was accompanied by a marked decrease in the expression of MYC, MYCN, AKT and an increase in p53 expression in neuroblastoma cell lines without TP53 mutation. In addition, S(+)-ibuprofen enhanced the expression of some favorable neuroblastoma genes (EPHB6, CD44) and genes involved in growth suppression and differentiation (EGR1, EPHA2, NRG1 and SEL1L). Gene expression profile and Ingenuity pathway analyses using TP53-mutated SKNAS cells further revealed that S(+)-ibuprofen suppressed molecular pathways associated with cell growth and conversely enhanced those of cell cycle arrest and the unfolded protein response. Collectively, these results suggest that S(+)-ibuprofen or its related compounds may have the potential for therapeutic and/or palliative use for unfavorable neuroblastoma.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Ikegaki
authors.forename: Sakeenah L
authors.initials: SL
authors.lastname: Hicks
authors.forename: Paul L
authors.initials: PL
authors.lastname: Regan
authors.forename: Joshua
authors.initials: J
authors.lastname: Jacobs
authors.forename: Amina S
authors.initials: AS
authors.lastname: Jumbo
authors.forename: Payton
authors.initials: P
authors.lastname: Leonhardt
authors.forename: Eric F
authors.initials: EF
authors.lastname: Rappaport
authors.forename: Xao X
authors.initials: XX
authors.lastname: Tang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis*; D051058:Oncogene Protein v-akt / Q000096:biosynthesis*; D015513:Oncogene Proteins / Q000096:biosynthesis*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D014408:Biomarkers, Tumor; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051058:Oncogene Protein v-akt; D007052:Ibuprofen