Lonidamine potentiates the oncolytic efficiency of M1 virus independent of hexokinase 2 but via inhibition of antiviral immunity.
Lonidamine potentiates the oncolytic efficiency of M1 virus independent of hexokinase 2 but via inhibition of antiviral immunity.
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Lonidamine 不依赖于己糖激酶 2，而是通过抑制抗病毒免疫来增强 M1 病毒的溶瘤效率。
DOI：
10.1186/s12935-020-01598-w
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发表时间：
2020-11-02
影响因子：
5.8
通讯作者：
Liang J
中科院分区：
文献类型：
--
作者：
Cai J;Zhu W;Lin Y;Hu J;Liu X;Xu W;Liu Y;Hu C;He S;Gong S;Yan G;Liang J
病毒是专性寄生虫，依赖宿主细胞提供成功感染所需的能量和分子前体。病毒诱导的代谢重编程的主要组成部分是糖酵解的激活，糖酵解为病毒复制提供生物分子资源。然而，很少有人知道溶瘤病毒和宿主糖酵解过程之间的串扰。采用MTT法检测M1病毒诱导的细胞杀伤作用。流式细胞术用于监测表达GFP报告基因的M1病毒的感染。采用qPCR和western blotting检测基因表达。进行RNA测序以评估不同药物处理下的基因表达。进行扫描电子显微镜以观察内质网（ER）。检测Caspase活性。最后，建立了小鼠异种移植瘤模型，以评价体内抗肿瘤作用。大多数数据采用双尾Student t检验或单因素ANOVA和Dunnett检验进行成对比较。通过ANOVA的重复测量分析肿瘤体积。使用Wilcoxon符号秩检验比较非正态分布数据。在这里，我们表明，葡萄糖类似物2-脱氧-d-葡萄糖（2-DG）抑制感染的M1病毒，我们确定为一种新型的溶瘤病毒，并降低其溶瘤效果，表明M1复制糖酵解的依赖性。与此相反，氯尼达明，一种已报道的己糖激酶2（HK 2）抑制剂，增强了M1病毒的感染和溶瘤作用，与HK 2无关。进一步的转录组学分析显示，抗病毒免疫应答的下调有助于氯尼达明介导的增强M1病毒的感染和溶瘤作用，并且MYC是氯尼达明抑制的抗病毒免疫应答因子库中的关键因子。此外，氯尼达明加强不可逆的ER应激介导的细胞凋亡由M1病毒。体内实验表明氯尼达明能增强M1的溶瘤作用。这项研究证明了M1病毒对糖酵解的依赖性，并确定了M1病毒治疗的候选药物。
Viruses are obligate parasites that depend on host cells to provide the energy and molecular precursors necessary for successful infection. The main component of virus-induced metabolic reprogramming is the activation of glycolysis, which provides biomolecular resources for viral replication. However, little is known about the crosstalk between oncolytic viruses and host glycolytic processes. A MTT assay was used to detect M1 virus-induced cell killing. Flow cytometry was used to monitor infection of M1 virus expressing the GFP reporter gene. qPCR and western blotting were used to detect gene expression. RNA sequencing was performed to evaluate gene expression under different drug treatments. Scanning electron microscopy was performed to visualize the endoplasmic reticulum (ER). Caspase activity was detected. Last, a mouse xenograft model was established to evaluate the antitumor effect in vivo. Most data were analyzed with a two-tailed Student’s t test or one-way ANOVA with Dunnett’s test for pairwise comparisons. Tumor volumes were analyzed by repeated measures of ANOVA. The Wilcoxon signed-rank test was used to compare nonnormally distributed data. Here, we showed that the glucose analog 2-deoxy-d-glucose (2-DG) inhibited infection by M1 virus, which we identified as a novel type of oncolytic virus, and decreased its oncolytic effect, indicating the dependence of M1 replication on glycolysis. In contrast, lonidamine, a reported hexokinase 2 (HK2) inhibitor, enhanced the infection and oncolytic effect of M1 virus independent of HK2. Further transcriptomic analysis revealed that downregulation of the antiviral immune response contributes to the lonidamine-mediated potentiation of the infection and oncolytic effect of M1 virus, and that MYC is the key factor in the pool of antiviral immune response factors inhibited by lonidamine. Moreover, lonidamine potentiated the irreversible ER stress-mediated apoptosis induced by M1 virus. Enhancement of M1′s oncolytic effect by lonidamine was also identified in vivo. This research demonstrated the dependence of M1 virus on glycolysis and identified a candidate synergist for M1 virotherapy.
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DOI：
10.1038/mt.2011.276
发表时间：
2012-04
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
影响因子：
21.3
作者：
Farassati, F;Yang, AD;Lee, PWK
通讯作者：
Lee, PWK
影响因子：
8
作者：
通讯作者：
--
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
29
作者：
Thai M;Graham NA;Braas D;Nehil M;Komisopoulou E;Kurdistani SK;McCormick F;Graeber TG;Christofk HR
通讯作者：
Christofk HR