Prostaglandin E2 promotes MYCN non-amplified neuroblastoma cell survival via ß-catenin stabilization.
J Cell Mol Med
; 19(1): 210-26, 2015 Jan.
Article
em En
| MEDLINE
| ID: mdl-25266063
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 ß-catenin as two novel players in neuroblastoma. Here, we aimed to define the potential role of PGE2 and cAMP and its potential interplay with ß-catenin, both of which may converge on neuroblastoma cell behaviour. Gain and loss of ß-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 3ß inhibition, ß-catenin phosphorylation at the protein kinase A target residue ser675, ß-catenin nuclear translocation and TCF-dependent gene transcription. Ectopic expression of a degradation-resistant ß-catenin mutant enhances neuroblastoma cell viability and inhibition of ß-catenin with XAV939 prevented PGE2 -induced cell viability. Finally, we show increased ß-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 ß-catenin stabilization, and suggest that this pathway is of relevance to high-risk neuroblastoma without MYCN amplification.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Nucleares
/
Dinoprostona
/
Amplificação de Genes
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Proteínas Oncogênicas
/
Beta Catenina
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Neuroblastoma
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
/
Adult
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Child
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Child, preschool
/
Female
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Humans
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Infant
/
Male
Idioma:
En
Revista:
J Cell Mol Med
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Holanda