Abstract
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.
Highlights
Viruses are obligate parasites that depend on host cells to provide the energy and molecular precursors necessary for successful infection
Phase contrast and immunofluorescence microscopy showed that 2-DG suppressed M1 infection and decreased M1-induced cytopathic effects (Fig. 1d, e). Consistent with this result, 2-DG reduced the infection rate of M1 virus, as shown by flow cytometry to determine the percentage of GFP-positive cells (Fig. 1f ). These results suggest that the infection and replication of M1 virus in tumor cells are dependent on the glycolysis in the host cells
Lonidamine did not affect IFN-α production but did inhibit the response of the antiviral signaling cascade to IFN-α (Fig. 2b−f ). These results indicate that lonidamine attenuates the IFN-mediated innate immune response of cancer cells, which may result in enhancement of the infection, replication and oncolytic effect of M1 virus
Summary
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. Oncolytic viruses are natural or genetically engineered organisms, and they constitute an ideal therapeutic platform for treating tumor patients on the basis of their. The antitumor mechanisms of oncolytic viruses include direct cell lysis and modulation of the tumor microenvironment (TME). Selective replication of oncolytic viruses in tumor cells induces immunogenic cell death, resulting in the release of antigens and danger-associated molecular patterns (DAMPs) that subsequently activate both innate and adaptive immune responses, converting immunologically “cold” tumors to “hot” ones that harbor high levels of tumor-infiltrating lymphocytes, tumor antigens and mutational burden. The heating of “cold” tumors by oncolytic viruses makes these viruses an ideal platform to combine with immune checkpoint inhibitors, which target immunologically “hot” tumors [3]. Numerous clinical trials are underway with oncolytic virus monotherapy or combination therapy with other antitumor drugs [5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
