Abstract
BackgroundProstaglandin 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 FindingsA 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.ConclusionsThese 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.
Highlights
Inflammatory cells and mediators are critical components of the tumor microenvironment
These findings demonstrate that Prostaglandin E2 (PGE2) acts as an autocrine and/or paracrine survival factor for neuroblastoma cells
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
Summary
Inflammatory cells and mediators are critical components of the tumor microenvironment. Arachidonic acid-derived lipid mediators are very potent signaling molecules that are important in the inflammatory process and implicated in tumorigenesis. Therapeutic inhibition of the COX enzymes in neuroblastoma induces apoptosis, suppresses tumor growth, reduces angiogenesis and potentiates the toxic effect of cytostatic drugs [3,5,6,7]. Inhibition of this pathway may represent a novel treatment strategy for neuroblastoma patients not cured today. 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. 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
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