Neuroblastoma cell proliferation involves prostaglandin E2 and subsequent β‐catenin stabilization

Abstract

Neuroblastoma (NBL) is a neural crest derived tumor which accounts for ±15% of pediatric cancer deaths. Despite recent efforts to elucidate the genetic background of NBL, the molecular etiology remains unclear. Recent evidence points to the cyclic‐ AMP (cAMP) elevating ligand prostaglandin E2 (PGE2) and the oncoprotein β‐catenin as two novel players in NBL. Here, we aimed to define a potential role and interplay of PGE2 and β‐catenin in survival of NBL.β‐Catenin expression was analyzed by immunohistochemistry in 41 human NBL biopsies. Further, we studied survival of 8 human NBL cell lines in response to PGE2 and cAMP elevation by the adenylyl cyclase activator forskolin.Our findings show that β‐catenin expression inversely correlates with NBL patient survival. In addition, we show that expression of a degradation‐resistant β‐catenin mutant (S33Y) increased NBL cell proliferation. Similarly, both PGE2 and forskolin enhanced proliferation, promoted GSK‐3 phosphorylation, β‐catenin stabilization and β‐catenin dependent gene transcription. In line with our hypothesis, reduction of endogenous PGE2 by a cyclooxygenase‐2 inhibitor attenuated NBL cell survival, a process being partially reversed by exogenous PGE2. We conclude that PGE2‐induced cAMP stabilizes β‐catenin and promotes NBL tumor cell survival via enhanced β‐catenin target gene transcription.This study is supported by the UMCG.