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Metabolic Imprint of Poliovirus on Glioblastoma Cells and Its Role in Virus Replication and Cytopathic Activity
Martin A Zenov1, Dmitry V Yanvarev1, Olga N Ivanova1
1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
Abstract:
Poliovirus represents an oncolytic agent for human glioblastoma-one of the most aggressive types of cancer. Since interference of viruses with metabolic and redox pathways is often linked to their pathogenesis, drugs targeting metabolic enzymes are regarded as potential enhancers of oncolysis. Our goal was to reveal an imprint of poliovirus on the metabolism of glioblastoma cell lines and to assess the dependence of the virus on these pathways. Using GC-MS, HPLC, and Seahorse techniques, we show that poliovirus interferes with amino acid, purine and polyamine metabolism, mitochondrial respiration, and glycolysis. However, many of these changes are cell line- and culture medium-dependent. 2-Deoxyglucose, the pharmacologic inhibitor of glycolysis, was shown to enhance the cytopathic effect of poliovirus, pointing to its possible repurposing as an enhancer of oncolysis. Inhibitors of polyamine biosynthesis, pyruvate import into mitochondria, and fatty acid oxidation exhibited antiviral activity, albeit in a cell-dependent manner. We also demonstrate that poliovirus does not interfere with the production of superoxide anions or with levels of H2O2, showing an absence of oxidative stress during infection. Finally, we showed that a high rate of poliovirus replication is associated with fragmentation of the mitochondrial network, pointing to the significance of these organelles for the virus.
Insights
Poliovirus alters glioblastoma cell metabolism, impacting amino acid, purine, and polyamine pathways. Glycolysis inhibition enhances poliovirus oncolysis, suggesting drug repurposing for cancer therapy.
Area of Science:
- Virology
- Oncology
- Metabolomics
Background:
- Poliovirus shows oncolytic potential against glioblastoma.
- Viral interference with host metabolism can enhance oncolysis.
- Targeting metabolic pathways is a strategy to boost oncolytic virotherapy.
Purpose of the Study:
- To investigate poliovirus's impact on glioblastoma cell metabolism.
- To determine glioblastoma cell pathways essential for poliovirus replication.
- To explore metabolic inhibitors as enhancers of poliovirus oncolysis.
Main Methods:
- Gas chromatography-mass spectrometry (GC-MS)
- High-performance liquid chromatography (HPLC)
- Seahorse XF analysis
- Assessment of viral cytopathic effects
Main Results:
- Poliovirus alters amino acid, purine, polyamine metabolism, glycolysis, and mitochondrial respiration in glioblastoma cells.
- Metabolic changes are dependent on cell line and culture medium.
- 2-Deoxyglucose enhances poliovirus cytopathic effects.
- Inhibitors of polyamine biosynthesis, pyruvate import, and fatty acid oxidation show antiviral activity in a cell-dependent manner.
- Poliovirus infection does not induce oxidative stress.
- High poliovirus replication correlates with mitochondrial network fragmentation.
Conclusions:
- Poliovirus significantly remodels glioblastoma cell metabolism.
- Glycolysis inhibition can enhance poliovirus oncolysis, indicating potential for drug repurposing.
- Mitochondrial integrity is crucial for poliovirus replication.
- Metabolic dependencies are cell-specific, requiring tailored therapeutic strategies.
