Academy of Medical Science, Zhengzhou University, Zhengzhou, China.
Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, USA.
Br J Pharmacol. 2023 Oct;180(20):2623-2640. doi: 10.1111/bph.16148. Epub 2023 Jun 28.
Glioblastoma (GBM) is the most aggressive brain tumour in the central nervous system, but the current treatment is very limited and unsatisfactory. PGE -initiated cAMP signalling via EP and EP receptors is involved in the tumourigenesis of multiple cancer types. However, whether or how EP and EP receptors contribute to GBM growth largely remains elusive.
We performed comprehensive data analysis of gene expression in human GBM samples and determined their expression correlations through multiple bioinformatics approaches. A time-resolved fluorescence energy transfer (TR-FRET) assay was utilized to characterize PGE -mediated cAMP signalling via EP and EP receptors in human glioblastoma cells. Using recently reported potent and selective small-molecule antagonists, we determined the effects of inhibition of EP and EP receptors on GBM growth in subcutaneous and intracranial tumour models.
The expression of both EP and EP receptors was upregulated and highly correlated with a variety of tumour-promoting cytokines, chemokines, and growth factors in human gliomas. Further, they were heterogeneously expressed in human GBM cells, where they compensated for each other to mediate PGE -initiated cAMP signalling and to promote colony formation, cell invasion and migration. Inhibition of EP and EP receptors revealed that these receptors might mediate GBM growth, angiogenesis, and immune evasion in a compensatory manner.
The compensatory roles of EP and EP receptors in GBM development and growth suggest that concurrently targeting these two PGE receptors might represent a more effective strategy than inhibiting either alone for GBM treatment.
胶质母细胞瘤（GBM）是中枢神经系统中最具侵袭性的脑肿瘤，但目前的治疗方法非常有限且效果不佳。前列腺素 E（PGE）通过 EP 和 EP 受体引发的环磷酸腺苷（cAMP）信号转导参与了多种癌症类型的肿瘤发生。然而，EP 和 EP 受体是否以及如何促进 GBM 生长在很大程度上仍不清楚。
我们对人类 GBM 样本中的基因表达进行了全面数据分析，并通过多种生物信息学方法确定了它们的表达相关性。我们利用时间分辨荧光能量转移（TR-FRET）测定法，研究了 PGE 通过 EP 和 EP 受体在人类神经胶质瘤细胞中诱导 cAMP 信号转导的情况。利用最近报道的高效且选择性的小分子拮抗剂，我们确定了抑制 EP 和 EP 受体对皮下和颅内肿瘤模型中 GBM 生长的影响。
EP 和 EP 受体的表达均上调，并与人类神经胶质瘤中的多种促进肿瘤生长的细胞因子、趋化因子和生长因子高度相关。此外，它们在人类 GBM 细胞中呈异质性表达，在这些细胞中，它们相互补偿以介导 PGE 引发的 cAMP 信号转导，并促进集落形成、细胞侵袭和迁移。抑制 EP 和 EP 受体表明，这些受体可能以补偿的方式介导 GBM 生长、血管生成和免疫逃逸。
EP 和 EP 受体在 GBM 发展和生长中的补偿作用表明，同时靶向这两个 PGE 受体可能比单独抑制任何一个受体更能有效治疗 GBM。
