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Optimization of oncolytic effect of Newcastle disease virus Clone30 by selecting sensitive tumor host and
Tianyan Liu1, Yu Zhang1, Yukai Cao1
1College of Life Science, Northeast Agricultural University, Harbin, 150030, China.
Abstract:
The direct oncolytic effect of Newcastle disease virus (NDV) depends on the following two aspects: the susceptibility of cancer cells to virus infection and the ability of virus itself to lyse cancer cells. First, we investigate the susceptibility of cancer cells to NDV infection, HepG2, MDA-MB-231, and SH-SY5Y cells were susceptible, A549, MCF7, and LoVo cells were less susceptible. To investigate the molecular mechanism responsible for cancer cell susceptibility, transcriptome sequencing was carried out. We found that the levels of alpha-sialic acid acyltransferase were upregulated in MDA-MB-231 cells compared with MCF7 cells, and the interferon was downregulated. Second, to optimize the oncolytic capacity of the wild-type rClone30, a series of chimeric viruses rClone30-Anh(HN), rClone30-Anh(F), and rClone30-Anh(HN-F) were constructed by exchanging the HN gene, F gene or both of non-lytic rClone30 strain with lytic strain Anhinga. rClone30-Anh(F) and rClone30-Anh(HN-F) enhanced the oncolytic effect of the rClone30, and this enhancement is more obvious in the susceptible cells. The oncolytic mechanism of rClone30-Anh(F) was analyzed by transcriptome analyses, in comparison with rClone30, rClone30-Anh(F) upregulated the expression of ATG5, Beclin 1, and MAP1LC3B, thus activating autophagy and promoting the production of syncytia. In conclusion, our study provides a strategy to enhance the oncolytic effect of rClone30.
Insights
Newcastle disease virus (NDV) shows direct oncolytic effects, with varied cancer cell susceptibility. Enhancing NDV through gene exchange boosts its cancer-lysing capacity, particularly in susceptible cells, by activating autophagy.
Area of Science:
- Virology
- Cancer Biology
- Molecular Oncology
Background:
- Newcastle disease virus (NDV) exhibits oncolytic potential.
- Cancer cell susceptibility and viral lysis ability are key to NDV's direct oncolytic effect.
- Understanding the molecular mechanisms underlying cancer cell susceptibility is crucial for optimizing NDV-based therapies.
Purpose of the Study:
- To investigate cancer cell susceptibility to NDV infection.
- To elucidate the molecular mechanisms of cancer cell susceptibility.
- To enhance the oncolytic capacity of a wild-type NDV strain (rClone30) through genetic modification.
Main Methods:
- Assessing susceptibility of various cancer cell lines (HepG2, MDA-MB-231, SH-SY5Y, A549, MCF7, LoVo) to NDV infection.
- Transcriptome sequencing to identify molecular differences in susceptible versus less susceptible cells.
- Construction of chimeric NDV viruses by exchanging genes (HN, F) with a lytic strain (Anhinga).
- Analyzing the oncolytic mechanism of enhanced NDV strains using transcriptome analysis.
Main Results:
- HepG2, MDA-MB-231, and SH-SY5Y cells were found to be susceptible to NDV, while A549, MCF7, and LoVo cells were less susceptible.
- Upregulation of alpha-sialic acid acyltransferase and downregulation of interferon were observed in susceptible MDA-MB-231 cells compared to MCF7 cells.
- Chimeric viruses rClone30-Anh(F) and rClone30-Anh(HN-F) demonstrated enhanced oncolytic effects, especially in susceptible cells.
- rClone30-Anh(F) activated autophagy by upregulating ATG5, Beclin 1, and MAP1LC3B, promoting syncytia formation.
Conclusions:
- Cancer cell susceptibility to NDV is variable and linked to specific molecular changes.
- Genetic modification of NDV, specifically through gene exchange (e.g., F gene), can significantly enhance its oncolytic efficacy.
- The enhanced oncolytic effect is mediated through mechanisms including autophagy activation and syncytia promotion, offering a promising strategy for improving NDV-based cancer therapy.
