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

Article date: June 2019

By: Jiange Qiu, Qianqian Li, Katherine A. Bell, Xue Yao, Yifeng Du, Erik Zhang, Jane J. Yu, Ying Yu, Zhi Shi, Jianxiong Jiang in Volume 176, Issue 11, pages 1680-1699

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.

DOI: 10.1111/bph.14622

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