Small-molecule inhibition of prostaglandin E receptor 2 impairs cyclooxygenase-associated malignant glioma growth
Small-molecule inhibition of prostaglandin E receptor 2 impairs cyclooxygenase-associated malignant glioma growth
复制标题
前列腺素 E 受体 2 的小分子抑制会损害环氧合酶相关的恶性胶质瘤生长
DOI：
10.1111/bph.14622
复制
发表时间：
2019
影响因子：
7.3
通讯作者：
Jiang Jianxiong
中科院分区：
文献类型：
--
作者：
Qiu Jiange;Li Qianqian;Bell Katherine A.;Yao Xue;Du Yifeng;Zhang Erik;Yu Jane J.;Yu Ying;Shi Zhi;Jiang Jianxiong
Background and PurposeAn 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 PGE2receptor subtype (i.e., EP1–EP4) directly contributes to COX activity‐promoted glioma growth remains largely unknown.Experimental ApproachUsing a publicly available database from The Cancer Genome Atlas research network, we compared the expression of PGE2signalling‐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 EP2receptor on glioma cell growth in vitro and in vivo.Key ResultsThe EP2receptor is a key Gαs‐coupled receptor that mediates COX‐2/PGE2‐initiated cAMP signalling pathways in human malignant glioma cells. Inhibition of EP2receptors 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 EP2antagonist in both subcutaneous and intracranial tumour models.Conclusion and ImplicationsTaken together, our results suggest that PGE2signalling via the EP2receptor increases the malignant potential of human glioma cells and might represent a novel therapeutic target for GBM.
