title: Prostaglandin E2 promotes MYCN non-amplified neuroblastoma cell survival via β-catenin stabilization.
abstract: Amplification of MYCN is the most well-known prognostic marker of neuroblastoma risk classification, but still is only observed in 25% of cases. Recent evidence points to the cyclic adenosine monophosphate (cAMP) elevating ligand prostaglandin E2 (PGE2 ) and β-catenin as two novel players in neuroblastoma. Here, we aimed to define the potential role of PGE2 and cAMP and its potential interplay with β-catenin, both of which may converge on neuroblastoma cell behaviour. Gain and loss of β-catenin function, PGE2 , the adenylyl cyclase activator forskolin and pharmacological inhibition of cyclooxygenase-2 (COX-2) were studied in two human neuroblastoma cell lines without MYCN amplification. Our findings show that PGE2 enhanced cell viability through the EP4 receptor and cAMP elevation, whereas COX-2 inhibitors attenuated cell viability. Interestingly, PGE2 and forskolin promoted glycogen synthase kinase 3β inhibition, β-catenin phosphorylation at the protein kinase A target residue ser675, β-catenin nuclear translocation and TCF-dependent gene transcription. Ectopic expression of a degradation-resistant β-catenin mutant enhances neuroblastoma cell viability and inhibition of β-catenin with XAV939 prevented PGE2 -induced cell viability. Finally, we show increased β-catenin expression in human high-risk neuroblastoma tissue without MYCN amplification. Our data indicate that PGE2 enhances neuroblastoma cell viability, a process which may involve cAMP-mediated β-catenin stabilization, and suggest that this pathway is of relevance to high-risk neuroblastoma without MYCN amplification.
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands; Department of Paediatrics, Department of Pediatric Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Sepp R
authors.initials: SR
authors.lastname: Jansen
authors.forename: Rian
authors.initials: R
authors.lastname: Holman
authors.forename: Ilja
authors.initials: I
authors.lastname: Hedemann
authors.forename: Ewoud
authors.initials: E
authors.lastname: Frankes
authors.forename: Carolina R S
authors.initials: CR
authors.lastname: Elzinga
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
authors.forename: Eveline S
authors.initials: ES
authors.lastname: de Bont
authors.forename: Martina
authors.initials: M
authors.lastname: Schmidt
mesh_terms: D000293:Adolescent; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007223:Infant; D008297:Male; D050505:Mutant Proteins / Q000378:metabolism; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; C459801:MYCN protein, human; D050505:Mutant Proteins; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D051176:beta Catenin; D005576:Colforsin; D000242:Cyclic AMP; D015232:Dinoprostone
keywords: cyclic AMP; neuroblastoma; prostaglandin E2; β-catenin