水疱性口炎病毒基质蛋白靶向线粒体，重编程葡萄糖代谢，并增强对2-脱氧葡萄糖的敏感性在胶质母细胞瘤中的作用

Matrix Protein of Vesicular Stomatitis Virus Targets the Mitochondria, Reprograms Glucose Metabolism, and Sensitizes to 2-Deoxyglucose in Glioblastoma

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HUMAN GENE THERAPY

影响因子:4

分区:医学3区 / 生物工程与应用微生物2区遗传学3区医学：研究与实验3区

发表日期:2024 Oct

作者: Yi Zhou, Yongzhong Li, Jing Chenm, Kai Mei, Mingxiang Kang, Ping Chen, Qiu Li

DOI: 10.1089/hum.2024.002

摘要

癌症治疗的潜在策略是同时靶向氧化磷酸化和糖酵解。水疱性口炎病毒（VSV）基质蛋白（VSV MP）可以靶向线粒体表面，引起形态学变化，这可能与线粒体功能障碍和氧化磷酸化抑制有关。既往研究表明，线粒体异常可以引导葡萄糖代谢向糖酵解方向转变。因此，在VSV MP处理后，为了完全阻断葡萄糖代谢并清除癌细胞，必须抑制糖酵解。在本研究中，采用合成葡萄糖类似物2-脱氧-D-葡萄糖（2-DG）与VSV MP联合用药，以治疗癌症。旨在探究VSV MP如何影响癌细胞的葡萄糖能量代谢，并评估2-DG与VSV联合时的协同作用。结果显示，在U87及C6胶质母细胞瘤系中，VSV MP引起线粒体膜电位下降、细胞色素c释放及葡萄糖能量代谢重编程。与2-DG联合后，VSV MP协同增强了细胞活力的下降、凋亡和G2/M期阻滞。同时，联合治疗加剧了ATP耗竭，激活了AMPK，并抑制了哺乳动物雷帕霉素靶蛋白（mTOR）信号通路。此外，单独2-DG处理在胶质母细胞瘤细胞中诱导自噬；然而，在联合治疗中，VSV MP抑制了由2-DG引起的自噬，最终增强了联合策略的细胞毒性作用。在异位U87胶质母细胞瘤模型和皮下C6胶质母细胞瘤模型中，联合治疗显著促使肿瘤缩小并延长了生存期。VSV MP与糖酵解抑制剂的联合可能成为治疗胶质母细胞瘤的有效新疗法。

Abstract

A potential therapeutic approach for cancer treatment is target oxidative phosphorylation and glycolysis simultaneously. The matrix protein of vesicular stomatitis virus (VSV MP) can target the surface of mitochondria, causing morphological changes that may be associated with mitochondrial dysfunction and oxidative phosphorylation inhibition. Previous research has shown that mitochondrial abnormalities can direct glucose metabolism toward glycolysis. Thus, after treatment with VSV MP, glycolysis inhibition is necessary to completely block glucose metabolism and eradicate cancer. Here, to inhibit glycolysis, the 2-deoxy-D-glucose (2-DG), a synthetic glucose analog was used to combine with VSV MP to treat cancer. This study aims to determine how VSV MP affects the glucose bioenergetic metabolism of cancer cells and to evaluate the synergistic effect of 2-DG when combined with VSV. Our results indicated that in U87 and C6 glioblastoma cell lines, VSV MP caused mitochondrial membrane potential loss, cytochrome c release, and glucose bioenergetics metabolism reprogramming. When combined with 2-DG, VSV MP synergistically aggravated cell viability, apoptosis, and G2/M phase arrest. Meanwhile, the combination therapy exacerbated ATP depletion, activated AMPK, and inhibited mammalian target of rapamycin signaling pathways. In addition, 2-DG treatment alone induced autophagy in glioblastoma cells; however, VSV MP inhibited the autophagy induced by 2-DG in combined treatment and finally contributed to the enhanced cytotoxic effect of the combination strategy in U87 and C6 cancer cells. In the orthotopic U87 glioblastoma model and subcutaneous C6 glioblastoma model, the combined treatment led to significant tumor regression and prolonged survival. A potent therapeutic approach for treating glioblastoma may be found in the combination of VSV MP and glycolytic inhibitors.