Lonidamine potentiates the oncolytic efficiency of M1 virus independent of hexokinase 2 but via inhibition of antiviral immunity

Cancer Cell International

Ying Liu¹  Jun Hu²  Jiankai Liang²  Guangmei Yan²  Wenbo Zhu²  Xincheng Liu²  Yuan Lin²  Jing Cai²  Cheng Hu³  Shoufang Gong⁴  Songmin He⁴  Wencang Xu⁴ 

[1] Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, 510630, Guangzhou, China;Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, 74 Zhongshan Road II, 510080, Guangzhou, China;Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, 510630, Guangzhou, China;Guangzhou Virotech Pharmaceutical Co., Ltd., 510663, Guangzhou, China;

关键词: Oncolytic virus;    M1 virus;    Lonidamine;    Glycolysis;    Colorectal carcinoma;    Antiviral immunity;   

DOI  :  10.1186/s12935-020-01598-w

来源: Springer

【 摘 要 】

BackgroundViruses 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.MethodsA 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.ResultsHere, 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.ConclusionsThis research demonstrated the dependence of M1 virus on glycolysis and identified a candidate synergist for M1 virotherapy.

【 授权许可】

CC BY