Prostaglandin E 2 promotes MYCN non‐amplified neuroblastoma cell survival via β‐catenin stabilization

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 E 2 ( PGE 2 ) and β‐catenin as two novel players in neuroblastoma. Here, we aimed to define the potential role of PGE 2 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, PGE 2 , 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 PGE 2 enhanced cell viability through the EP 4 receptor and cAMP elevation, whereas COX ‐2 inhibitors attenuated cell viability. Interestingly, PGE 2 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 XAV 939 prevented PGE 2 ‐induced cell viability. Finally, we show increased β‐catenin expression in human high‐risk neuroblastoma tissue without MYCN amplification. Our data indicate that PGE 2 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.