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

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.

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.

The EP₂ receptor is a key Gα_s -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.

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.