Wei Zi-Long, Han Shuo, Han Dong-Hua, Li Xue-Tao, Huang Yu-Lun, Wang Zhi-Min
Department of Neurosurgery, The Fourth Hospital Affiliated to Soochow University, Suzhou Dushu Lake Hospital, Suzhou, 215000, China.
Department of Neurosurgery, Shanghai Pudong Hospital Affliated to Fudan University, Pudong Medical Center, Shanghai, 201399, China.
Biochem Biophys Rep. 2025 May 13;42:102048. doi: 10.1016/j.bbrep.2025.102048. eCollection 2025 Jun.
Glioblastoma multiform (GBM) constitutes approximately 14.7 % of all central nervous system tumors (CNSTs) and 45.2 % of primary malignant CNSTs. Extensive research has indicated that β-arrestin 1 (ARRB1) plays a significant role in tumor malignancy. In this investigation, we established GBM cell lines representing normal control (NC), overexpression (OE) and Δexon13 GBM variants (△exon13) of ARRB1. Our findings indicate that the ARRB1-OE isoform facilitated GBM cell proliferation and migration, with the ARRB1-△exon13 isoform further augmenting this effect. Notably, the isoform ARRB1-△exon13 binds to glycolytic proteins including ENO1 and ALDOA and regulates glycolysis. In vivo studies corroborate the tumor-promoting effects of ARRB1-Δexon13. Furthermore, we demonstrate that 2-DG effectively inhibits the malignancy-promoting capabilities of ARRB1-Δexon13 by reducing pyruvate levels. Our identification of alternative RNA splicing events of ARRB1 reveals a mechanism by which GBM cell malignancy is augmented through ARRB1-Δexon13, which mediates glycolysis-related pathways.
多形性胶质母细胞瘤（GBM）约占所有中枢神经系统肿瘤（CNST）的14.7%，占原发性恶性CNST的45.2%。广泛的研究表明，β-抑制蛋白1（ARRB1）在肿瘤恶性程度中起重要作用。在本研究中，我们建立了代表正常对照（NC）、过表达（OE）和ARRB1的Δexon13 GBM变体（△exon13）的GBM细胞系。我们的研究结果表明，ARRB1-OE异构体促进了GBM细胞的增殖和迁移，而ARRB1-△exon13异构体进一步增强了这种作用。值得注意的是，异构体ARRB1-△exon13与包括ENO1和ALDOA在内的糖酵解蛋白结合并调节糖酵解。体内研究证实了ARRB1-Δexon13的促肿瘤作用。此外，我们证明2-DG通过降低丙酮酸水平有效抑制ARRB1-Δexon13的促恶性能力。我们对ARRB1可变RNA剪接事件的鉴定揭示了一种机制，即GBM细胞恶性程度通过ARRB1-Δexon13增强，ARRB1-Δexon13介导糖酵解相关途径。
