文章：

推测性S1PR1调节剂ACT-209905在体外抑制胶质母细胞瘤细胞的生长与迁移

The Putative S1PR1 Modulator ACT-209905 Impairs Growth and Migration of Glioblastoma Cells In Vitro

原文发布日期：26 August 2023

DOI: 10.3390/cancers15174273

类型: Article

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英文摘要：

Glioblastoma (GBM) is still a deadly tumor due to its highly infiltrative growth behavior and its resistance to therapy. Evidence is accumulating that sphingosine-1-phosphate (S1P) acts as an important tumor-promoting molecule that is involved in the activation of the S1P receptor subtype 1 (S1PR1). Therefore, we investigated the effect of ACT-209905 (a putative S1PR1 modulator) on the growth of human (primary cells, LN-18) and murine (GL261) GBM cells. The viability and migration of GBM cells were both reduced by ACT-209905. Furthermore, co-culture with monocytic THP-1 cells or conditioned medium enhanced the viability and migration of GBM cells, suggesting that THP-1 cells secrete factors which stimulate GBM cell growth. ACT-209905 inhibited the THP-1-induced enhancement of GBM cell growth and migration. Immunoblot analyses showed that ACT-209905 reduced the activation of growth-promoting kinases (p38, AKT1 and ERK1/2), whereas THP-1 cells and conditioned medium caused an activation of these kinases. In addition, ACT-209905 diminished the surface expression of pro-migratory molecules and reduced CD62P-positive GBM cells. In contrast, THP-1 cells increased the ICAM-1 and P-Selectin content of GBM cells which was reversed by ACT-209905. In conclusion, our study suggests the role of S1PR1 signaling in the growth of GBM cells and gives a partial explanation for the pro-tumorigenic effects that macrophages might have on GBM cells.

摘要翻译： 

胶质母细胞瘤（GBM）因其高度浸润性生长特性及治疗抵抗性，仍是一种致命性肿瘤。越来越多的证据表明，鞘氨醇-1-磷酸（S1P）作为重要的促肿瘤分子，通过激活S1P受体亚型1（S1PR1）发挥作用。本研究探讨了ACT-209905（一种推定S1PR1调节剂）对人源（原代细胞LN-18）及鼠源（GL261）GBM细胞生长的影响。结果显示，ACT-209905可同时抑制GBM细胞活力与迁移能力。与单核细胞THP-1共培养或其条件培养基能增强GBM细胞活力与迁移，提示THP-1细胞分泌促进GBM细胞生长的因子，而ACT-209905可抑制这种THP-1诱导的生长与迁移增强效应。免疫印迹分析表明，ACT-209905降低了促生长激酶（p38、AKT1和ERK1/2）的活化水平，而THP-1细胞及其条件培养基则激活了这些激酶。此外，ACT-209905降低了促迁移分子的表面表达，并减少了CD62P阳性GBM细胞比例；相反，THP-1细胞能增加GBM细胞ICAM-1和P-选择素表达，该效应可被ACT-209905逆转。本研究揭示了S1PR1信号通路在GBM细胞生长中的作用，并部分解释了巨噬细胞可能对GBM细胞产生的促肿瘤效应。

原文链接：

The Putative S1PR1 Modulator ACT-209905 Impairs Growth and Migration of Glioblastoma Cells In Vitro