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

Abstract

Background and Purpose: An up-regulation of COX-2 in malignant gliomas causes excessive synthesis of PGE2, which is thought to facilitate brain tumour 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 research network, we compared the expression of PGE2 signalling-associated genes in human lower grade glioma and glioblastoma multiforme (GBM) samples. The Kaplan–Meier analysis was performed to determine the relationship between their expression and survival probability. A time-resolved FRET method was used to identify the EP subtype that mediates COX-2/PGE2-initiated cAMP signalling in human GBM cells. Taking advantage of a recently identified novel selective bioavailable brain-permeable small-molecule antagonist, we studied the effect of pharmacological inhibition of the EP2 receptor on glioma cell growth in vitro and in vivo. Key Results: The EP2 receptor is a key Gαs-coupled receptor that mediates COX-2/PGE2-initiated cAMP signalling pathways in human malignant glioma cells. Inhibition of EP2 receptors reduced COX-2 activity-driven GBM cell proliferation, invasion, and migration and caused cell cycle arrest at G0–G1 and apoptosis of GBM cells. Glioma cell growth in vivo was also substantially decreased by post-treatment with an EP2 antagonist in both subcutaneous and intracranial tumour models. Conclusion and Implications: Taken together, our results suggest that PGE2 signalling via the EP2 receptor increases the malignant potential of human glioma cells and might represent a novel therapeutic target for GBM.