囊泡气孔病毒的基质蛋白靶向线粒体，重编程葡萄糖代谢，并在胶质母细胞瘤中敏感到2-脱氧葡萄糖
Matrix Protein of Vesicular Stomatitis Virus Targets the Mitochondria, Reprograms Glucose Metabolism, and Sensitizes to 2-Deoxyglucose in Glioblastoma
影响因子:4.00000
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
摘要
癌症治疗的潜在治疗方法是同时靶向氧化磷酸化和糖酵解。囊泡口腔炎病毒（VSV MP）的基质蛋白可以靶向线粒体的表面，从而导致形态变化，可能与线粒体功能障碍和氧化磷酸化抑制有关。先前的研究表明，线粒体异常可以将葡萄糖代谢转向糖酵解。因此，在用VSV MP治疗后，必须完全阻断葡萄糖代谢和消除癌症是必要的。在这里，为了抑制糖酵解，2-脱氧-D-葡萄糖（2-DG），使用合成葡萄糖类似物与VSV MP结合以治疗癌症。这项研究旨在确定VSV MP如何影响癌细胞的葡萄糖生物能代谢，并在与VSV结合使用时评估2-DG的协同作用。我们的结果表明，在U87和C6胶质母细胞瘤细胞系中，VSV MP导致线粒体膜势损失，细胞色素C释放和葡萄糖生物能源代谢重编程。当与2-DG结合使用时，VSV MP协同加剧了细胞活力，凋亡和G2/M期停滞。同时，联合疗法加剧了ATP耗竭，激活的AMPK并抑制了雷帕霉素信号通路的哺乳动物靶标。此外，仅2-DG处理可引起胶质母细胞瘤细胞的自噬。然而，VSV MP抑制了在联合治疗中由2-DG诱导的自噬，最终导致了U87和C6癌细胞中组合策略的增强的细胞毒性作用。在原位U87胶质母细胞瘤模型和皮下C6胶质母细胞瘤模型中，联合治疗导致显着的肿瘤消退和延长生存率。在VSV MP和糖酵解抑制剂的组合中可以发现一种有效治疗胶质母细胞瘤的治疗方法。
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.