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Small-molecule inhibition of prostaglandin E receptor 2 impairs cyclooxygenase-associated malignant glioma growth.

BACKGROUND AND PURPOSE: Induced cyclooxygenase-2 (COX-2) in malignant gliomas causes excessive synthesis of prostaglandin E2 (PGE2 ) that is thought to facilitate the brain tumor growth and invasion. However, which downstream PGE2 receptor subtype (i.e., EP1-EP4) directly contributes to COX activity-promoted glioma growth remains largely unknown.

EXPERIMENTAL APPROACH: Using a publicly available database from The Cancer Genome Atlas (TCGA) research network, we compared the expression of PGE2 signaling-associated genes in human lower-grade glioma (LGG) and glioblastoma multiforme (GBM) samples. The Kaplan-Meier analysis was performed to determine the relationship between their expression and survival probability. A time-resolved fluorescence resonance energy transfer (TR-FRET) method was used to identify the PGE2 receptor subtype that mediates COX-2/PGE2 -initiated cAMP signaling in human GBM cells. Taking advantage of a novel selective bioavailable brain-permeable small-molecule antagonist that we recently reported, the effect of pharmacological inhibition of EP2 receptor on glioma cell growth in vitro and in vivo was studied.

KEY RESULTS: EP2 is a key Gαs -coupled receptor that mediates COX-2/PGE2 -initiated cAMP signal pathways in human malignant glioma cells. Inhibition of EP2 receptor reduces COX-2 activity-driven GBM cell proliferation, invasion and migration, and causes cell-cycle arrest at G0-G1 and apoptosis of the GBM cells. Glioma cell growth in vivo is also substantially decreased by post-treatment of the EP2 antagonist in both subcutaneous and intracranial tumor models.

CONCLUSION AND IMPLICATIONS: Our results together suggest that PGE2 signaling via EP2 receptor increases the malignant potential of human glioma cells and might represent a novel therapeutic target for GBM.

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