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白细胞介素-11/IL-11 受体通过增强谷氨酰胺分解促进葡萄糖饥饿条件下的胶质母细胞瘤存活和侵袭。

The Interleukin-11/IL-11 Receptor Promotes Glioblastoma Survival and Invasion under Glucose-Starved Conditions through Enhanced Glutaminolysis.

机构信息

Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3050, Australia.

Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia.

出版信息

Int J Mol Sci. 2023 Feb 8;24(4):3356. doi: 10.3390/ijms24043356.

DOI:10.3390/ijms24043356
PMID:36834778
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9960532/
Abstract

Glioblastoma cells adapt to changes in glucose availability through metabolic plasticity allowing for cell survival and continued progression in low-glucose concentrations. However, the regulatory cytokine networks that govern the ability to survive in glucose-starved conditions are not fully defined. In the present study, we define a critical role for the IL-11/IL-11Rα signalling axis in glioblastoma survival, proliferation and invasion when cells are starved of glucose. We identified enhanced IL-11/IL-11Rα expression correlated with reduced overall survival in glioblastoma patients. Glioblastoma cell lines over-expressing IL-11Rα displayed greater survival, proliferation, migration and invasion in glucose-free conditions compared to their low-IL-11Rα-expressing counterparts, while knockdown of IL-11Rα reversed these pro-tumorigenic characteristics. In addition, these IL-11Rα-over-expressing cells displayed enhanced glutamine oxidation and glutamate production compared to their low-IL-11Rα-expressing counterparts, while knockdown of IL-11Rα or the pharmacological inhibition of several members of the glutaminolysis pathway resulted in reduced survival (enhanced apoptosis) and reduced migration and invasion. Furthermore, IL-11Rα expression in glioblastoma patient samples correlated with enhanced gene expression of the glutaminolysis pathway genes GLUD1, GSS and c-Myc. Overall, our study identified that the IL-11/IL-11Rα pathway promotes glioblastoma cell survival and enhances cell migration and invasion in environments of glucose starvation via glutaminolysis.

摘要

胶质母细胞瘤细胞通过代谢可塑性适应葡萄糖供应变化，从而在低葡萄糖浓度下存活并继续增殖。然而，调节细胞在葡萄糖饥饿条件下存活能力的细胞因子网络尚未完全定义。在本研究中，我们发现 IL-11/IL-11Rα 信号轴在胶质母细胞瘤细胞葡萄糖饥饿时的存活、增殖和侵袭中起关键作用。我们发现，IL-11/IL-11Rα 表达增强与胶质母细胞瘤患者总生存率降低相关。与低表达 IL-11Rα 的细胞相比，过表达 IL-11Rα 的胶质母细胞瘤细胞系在无糖条件下表现出更强的存活、增殖、迁移和侵袭能力，而 IL-11Rα 的敲低则逆转了这些促肿瘤特性。此外，这些过表达 IL-11Rα 的细胞与低表达 IL-11Rα 的细胞相比，表现出增强的谷氨酰胺氧化和谷氨酸生成，而 IL-11Rα 的敲低或几种谷氨酰胺分解途径的药理学抑制导致存活（增强凋亡）减少以及迁移和侵袭减少。此外，在胶质母细胞瘤患者样本中，IL-11Rα 的表达与谷氨酰胺分解途径基因 GLUD1、GSS 和 c-Myc 的增强基因表达相关。总的来说，我们的研究表明，IL-11/IL-11Rα 通路通过谷氨酰胺分解促进胶质母细胞瘤细胞的存活，并增强细胞在葡萄糖饥饿环境中的迁移和侵袭。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfe3/9960532/a371369fc1ce/ijms-24-03356-g006.jpg
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