Inhibition of glioblastoma cell proliferation and invasion by the choline-kinase inhibitor JAS239 varies with cell type and hypoxia.
Inhibition of glioblastoma cell proliferation and invasion by the choline-kinase inhibitor JAS239 varies with cell type and hypoxia.
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胆碱激酶抑制剂 JAS239 对胶质母细胞瘤细胞增殖和侵袭的抑制作用因细胞类型和缺氧而异。
DOI：
10.1101/2024.01.17.576078
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Poptani,Harish
中科院分区：
文献类型：
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作者：
LouiseKelly,Claire;Wydrzynska,Martyna;Phelan,MarieM;Osharovich,Sofya;Delikatny,EdwardJ;Sée,Violaine;Poptani,Harish
背景：在包括胶质母细胞瘤（GBM）在内的大多数实体肿瘤中都观察到高水平的胆碱激酶α (ChoK)，然而直到最近，ChoK抑制剂在GBM模型中显示出有限的疗效。鉴于缺氧与GBM治疗抵抗有关，我们假设肿瘤缺氧可能是造成这种限制的原因。因此，我们在GBM细胞中评估了缺氧对JAS239（一种有效的ChoK抑制剂）功能的影响。方法小鼠（F98和9L）和人（U-87 MG和U-251 MG） GBM细胞系缺氧72 h， JAS239处理24 h。进行核磁共振代谢组学测量和分析以评估所涉及的信号通路。此外，在常氧或低氧细胞中，在加或不加JAS239处理的情况下，在细胞单层和三维球体中测量细胞增殖、细胞周期进展和细胞侵袭，以评估缺氧如何影响JAS239的功能。结果缺氧和JAS239处理导致细胞代谢途径的显著变化，特别是磷脂和糖酵解途径，通过诱导细胞周期阻滞导致细胞增殖减少。有趣的是，JAS239也削弱了GBM的侵袭。然而，JAS239的作用因细胞系而异，反映了在GBMs中观察到的固有异质性。结论JAS239与缺氧可调节细胞代谢，抑制细胞增殖，改变细胞侵袭。这些结果可能有助于设计基于ChoK抑制的新治疗策略，该策略可以作用于多种促肿瘤特征。
BackgroundElevated choline kinase alpha (ChoK) is observed in most solid tumours including glioblastomas (GBM), yet until recently, inhibitors of ChoK have demonstrated limited efficacy in GBM models. Given that hypoxia is associated with GBM therapy resistance, we hypothesised that tumour hypoxia could be responsible for such limitations. We therefore evaluated in GBM cells, the effect of hypoxia on the function of JAS239, a potent ChoK inhibitor.MethodsRodent (F98 and 9L) and human (U-87 MG and U-251 MG) GBM cell lines were subjected to 72 hours of hypoxia conditioning and treated with JAS239 for 24 hours. NMR metabolomic measurements and analyses were performed to evaluate the signalling pathways involved. In addition, cell proliferation, cell cycle progression and cell invasion were measured in cell monolayers and 3D spheroids, with or without JAS239 treatment in normoxic or hypoxic cells to assess how hypoxia affects JAS239 function.ResultsHypoxia and JAS239 treatment led to significant changes in the cellular metabolic pathways, specifically the phospholipid and glycolytic pathways associated with a reduction in cell proliferation via induced cell cycle arrest. Interestingly, JAS239 also impaired GBM invasion. However, JAS239 effects were variable depending on the cell line, reflecting the inherent heterogeneity observed in GBMs.ConclusionOur findings indicate that JAS239 and hypoxia can deregulate cellular metabolism, inhibit proliferation and alter cell invasion. These results may be useful for the design of new therapeutic strategies based on ChoK inhibition that can act on multiple pro-tumorigenic features.