LAUSR

BACKGROUND AND PURPOSE Glioblastoma (GBM) is the most aggressive brain tumor in the central nervous system, but the current treatment is very limited and overall unsatisfactory. PGE2 -initiated cAMP signaling via EP2 and EP4 receptors is involved in the tumorigenesis of multiple cancer types. However, whether or how EP2 and EP4 contribute to GBM growth largely remains elusive. EXPERIMENTAL APPROACH We performed comprehensive data analyses of gene expression in human GBM samples and determined their expression correlations through multiple bioinformatics approaches. A time-resolved fluorescence energy transfer (TR-FRET) assay was utilized to characterize the PGE2 -mediated cAMP signaling via EP2 and EP4 receptors in human glioblastoma cells. Taking advantage of potent and selective small-molecule antagonists that were recently reported, we determined the effects of pharmacological inhibition of EP2 or EP4 on GBM growth in both subcutaneous and intracranial tumor models. KEY RESULTS The expression of both EP2 and EP4 receptors were upregulated and highly correlated with a variety of tumor-promoting cytokines, chemokines, and growth factors in human gliomas. Further, they were heterogeneously expressed in human GBM cells, where they compensated each other to mediate PGE2 -initiated cAMP signaling and to promote colony formation, cell invasion and migration. Pharmacological inhibition of EP2 and EP4 revealed that these two PGE2 receptors might mediate GBM growth, angiogenesis, and immune evasion in a compensatory manner. CONCLUSION AND IMPLICATIONS The compensatory roles of EP2 and EP4 in GBM development and growth suggest that concurrently targeting these two Gαs -coupled PGE2 receptors might represent a more effective strategy than inhibiting either EP2 or EP4 alone for GBM treatment.