Autocrine prostaglandin E2 signaling promotes tumor cell survival and proliferation in childhood neuroblastoma

Background

Prostaglandin E₂ (PGE₂) is an important mediator in tumor-promoting inflammation. High expression of cyclooxygenase-2 (COX-2) has been detected in the embryonic childhood tumor neuroblastoma, and treatment with COX inhibitors significantly reduces tumor growth. Here, we have investigated the significance of a high COX-2 expression in neuroblastoma by analysis of PGE₂ production, the expression pattern and localization of PGE₂ receptors and intracellular signal transduction pathways activated by PGE₂.

Principal Findings

A high expression of the PGE₂ receptors, EP1, EP2, EP3 and EP4 in primary neuroblastomas, independent of biological and clinical characteristics, was detected using immunohistochemistry. In addition, mRNA and protein corresponding to each of the receptors were detected in neuroblastoma cell lines. Immunofluorescent staining revealed localization of the receptors to the cellular membrane, in the cytoplasm, and in the nuclear compartment. Neuroblastoma cells produced PGE₂ and stimulation of serum-starved neuroblastoma cells with PGE₂ increased the intracellular concentration of calcium and cyclic AMP with subsequent phosphorylation of Akt. Addition of 16,16-dimethyl PGE₂ (dmPGE₂) increased cell viability in a time, dose- and cell line-dependent manner. Treatment of neuroblastoma cells with a COX-2 inhibitor resulted in a diminished cell growth and viability that was reversed by the addition of dmPGE₂. Similarly, PGE₂ receptor antagonists caused a decrease in neuroblastoma cell viability in a dose-dependent manner.

Conclusions

These findings demonstrate that PGE₂ acts as an autocrine and/or paracrine survival factor for neuroblastoma cells. Hence, specific targeting of PGE₂ signaling provides a novel strategy for the treatment of childhood neuroblastoma through the inhibition of important mediators of tumor-promoting inflammation.