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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 G?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. 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.

SUBMITTER: Qiu J 

PROVIDER: S-EPMC6514294 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Qiu Jiange J   Li Qianqian Q   Bell Katherine A KA   Yao Xue X   Du Yifeng Y   Zhang Erik E   Yu Jane J JJ   Yu Ying Y   Shi Zhi Z   Jiang Jianxiong J  

British journal of pharmacology 20190429 11


<h4>Background and purpose</h4>An up-regulation of COX-2 in malignant gliomas causes excessive synthesis of PGE<sub>2</sub> , which is thought to facilitate brain tumour growth and invasion. However, which downstream PGE<sub>2</sub> receptor subtype (i.e., EP<sub>1</sub> -EP<sub>4</sub> ) directly contributes to COX activity-promoted glioma growth remains largely unknown.<h4>Experimental approach</h4>Using a publicly available database from The Cancer Genome Atlas research network, we compared t  ...[more]

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