Department of Cell Biology and Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, Guangdong Provincial Key Laboratory of Bioengineering Medicine, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong, China.
Cell Signal Transduction and Proteomics Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
Br J Pharmacol. 2019 Jun;176(11):1680-1699. doi: 10.1111/bph.14622. Epub 2019 Apr 29.
An up-regulation of COX-2 in malignant gliomas causes excessive synthesis of PGE , which is thought to facilitate brain tumour growth and invasion. However, which downstream PGE receptor subtype (i.e., EP -EP ) 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 PGE 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/PGE -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 EP receptor on glioma cell growth in vitro and in vivo.
The EP receptor is a key Gα -coupled receptor that mediates COX-2/PGE -initiated cAMP signalling pathways in human malignant glioma cells. Inhibition of EP 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 EP antagonist in both subcutaneous and intracranial tumour models.
Taken together, our results suggest that PGE signalling via the EP receptor increases the malignant potential of human glioma cells and might represent a novel therapeutic target for GBM.
恶性神经胶质瘤中 COX-2 的上调导致 PGE 的过度合成，这被认为有助于脑肿瘤的生长和侵袭。然而，哪种下游 PGE 受体亚型（即 EP 受体）直接促进 COX 活性促进胶质瘤生长，在很大程度上仍不清楚。
利用癌症基因组图谱研究网络的公共数据库，我们比较了人类低级别神经胶质瘤和多形性胶质母细胞瘤（GBM）样本中与 PGE 信号相关的基因表达。进行 Kaplan-Meier 分析以确定其表达与生存概率之间的关系。采用时间分辨 FRET 方法鉴定介导 COX-2/PGE 启动的 cAMP 信号的 EP 亚型在人 GBM 细胞中。利用最近发现的新型选择性生物可利用的脑渗透小分子拮抗剂，我们研究了药理学抑制 EP 受体对体外和体内胶质瘤细胞生长的影响。
EP 受体是一种关键的 Gα 偶联受体，介导 COX-2/PGE 启动的 cAMP 信号通路在人类恶性神经胶质瘤细胞中。抑制 EP 受体可降低 COX-2 活性驱动的 GBM 细胞增殖、侵袭和迁移，并导致 GBM 细胞的细胞周期停滞在 G0-G1 期和凋亡。在皮下和颅内肿瘤模型中，用 EP 拮抗剂进行后处理也大大降低了胶质瘤细胞的生长。
综上所述，我们的结果表明，PGE 通过 EP 受体的信号转导增加了人类神经胶质瘤细胞的恶性潜能，可能代表 GBM 的一种新的治疗靶点。
