Oncolytic Virus-Induced Autophagy in Glioblastoma.

Abstract

Simple SummaryGlioblastoma (GBM) is the most common and aggressive brain tumor with an incidence rate of nearly 3.19/100,000. Current therapeutic options fall short in improving the survival of patients with GBM. Various genetic and microenvironmental factors contribute to GBM progression and resistance to therapy. The development of gene therapies using self-replicating oncolytic viruses can advance GBM treatment. Due to GBM heterogeneity, oncolytic viruses have been genetically modified to improve the antiglioma effect in vitro and in vivo. Oncolytic viruses can activate autophagy signaling in GBM upon tumoral infection. Autophagy can be cytoprotective, whereby the GBM cells catabolize damaged organelles to accommodate to virus-induced stress, or cytotoxic, whereby it leads to the destruction of GBM cells. Understanding the molecular mechanisms that control oncolytic virus-induced autophagic signaling in GBM can fuel further development of novel and more effective genetic vectors.Autophagy is a catabolic process that allows cells to scavenge damaged organelles and produces energy to maintain cellular homeostasis. It is also an effective defense method for cells, which allows them to identify an internalized pathogen and destroy it through the fusion of the autophagosome and lysosomes. Recent reports have demonstrated that various chemotherapeutic agents and viral gene therapeutic vehicles provide therapeutic advantages for patients with glioblastoma as monotherapy or in combination with standards of care. Despite nonstop efforts to develop effective antiglioma therapeutics, tumor-induced autophagy in some studies manifests tumor resistance and glioma progression. Here, we explore the functional link between autophagy regulation mediated by oncolytic viruses and discuss how intracellular interactions control autophagic signaling in glioblastoma. Autophagy induced by oncolytic viruses plays a dual role in cell death and survival. On the one hand, autophagy stimulation has mostly led to an increase in cytotoxicity mediated by the oncolytic virus, but, on the other hand, autophagy is also activated as a cell defense mechanism against intracellular pathogens and modulates antiviral activity through the induction of ER stress and unfolded protein response (UPR) signaling. Despite the fact that the moment of switch between autophagic prosurvival and prodeath modes remains to be known, in the context of oncolytic virotherapy, cytotoxic autophagy is a crucial mechanism of cancer cell death.