Abstract
Newcastle disease virus (NDV) strongly induces both type I and III antiviral interferons (IFNs-α/-β and IFN-λ, respectively) in tumor cells while it induces mainly type III IFN in normal cells. Impairment of antiviral type I IFN signaling in tumor cells is thought to be the reason for effective oncolysis. However, there is lack of clarity why lentogenic strain NDV can also induce oncolysis. NDV infection caused apoptosis in normal and tumor cells as demonstrated with the caspase-3 enzyme activation and annexin-V detection. The apoptosis response was inhibited by B18R protein (a type I IFN inhibitor) in tumor cells i.e. A549 and U87MG, and not in normal cells i.e. NB1RGB and HEK293. Similarly, UV-inactivated medium from NDV infection was shown to induce apoptosis in corresponding cells and the response was inhibited in A549 and U87MG cells with the addition of B18R protein. Treatment with combination of IFNs-α/-β/-λ or IFNs-α/-β or IFN-λ in NB1RGB, HEK293, A549 and U87MG showed that caspase activity in IFNs-α/-β/-λ group was the highest, followed with IFN-α/-β group and IFN-λ group. This suggests that tumor-selectivity of NDV is mainly because of the cumulative effect of type I and III in tumor cells that lead to higher apoptotic effect.
Highlights
Potential use of oncolytic viruses are being evaluated as anticancer agent due to their selective killing of tumor cells with the minimal damage to normal cells
Considering the potency of Newcastle disease virus (NDV) to be as a strong type I and III IFN inducers, with much stronger induction of type I IFN was observed in tumor cells[25]; in this study we investigate the effect of NDV-induced antiviral interferons to stimulate apoptosis in tumor cells
We demonstrated in the present work that oncolytic activity of NDV LaSota was a consequence of a selective induction of apoptosis in tumor cells despite the low virulence or low dose usage of the virus
Summary
Potential use of oncolytic viruses are being evaluated as anticancer agent due to their selective killing of tumor cells with the minimal damage to normal cells. Virus infection results in signals to release antiviral interferons (IFN)[11,12,13] These signals can be recognized by the membrane bound Toll-like receptors (TLR) that are involved in sensing viral glycoprotein, and the cytoplasmic RIG-like receptors (RLR) that is mainly responsible for sensing RNA viruses. This process activates transcription factors, most often interferon regulatory factor (IRF)[3], IRF7 and nuclear factor kappa B (NFκB), that subsequently initiates transcription and expression of IFNs type I and III12,14,15.
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