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.
Highlights
Neuroblastomas are heterogeneous tumours that vary to a large extent in prognosis and disease outcome and are responsible for 15% of all childhood cancer deaths [1]
To study the effects of cyclic adenosine monophosphate (cAMP) elevation on MYCN non-amplified neuroblastoma cell viability, SK-N-AS cells were incubated for the indicated periods of time with the direct adenylyl cyclase activator forskolin or prostaglandin E2 (PGE2) (Fig. 1A)
To clarify mechanisms underlying the reduction in cell survival by COX-2 inhibition, we studied cell cycle progression and apoptotic pathway activation
Summary
Neuroblastomas are heterogeneous tumours that vary to a large extent in prognosis and disease outcome and are responsible for 15% of all childhood cancer deaths [1]. Recent studies have focused on the link between proliferation, differentiation and programmed cell death in neuroblastoma, understanding of the molecu-. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. CAMP is involved in the regulation of diverse cellular processes, including regulation of cytoskeletal dynamics, cellular differentiation, proliferation and programmed cell death in a variety of cells including neural-like cells [10, 11] PGE2 binds to its membrane bound E-type prostanoid receptors, of which prostanoid receptors type 2 and 4 are known to couple to Gas and are thereby able to increase intracellular cyclic adenosine monophosphate (cAMP) levels. cAMP is involved in the regulation of diverse cellular processes, including regulation of cytoskeletal dynamics, cellular differentiation, proliferation and programmed cell death in a variety of cells including neural-like cells [10, 11]
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