RETRACTED ARTICLE: Optimization of oncolytic effect of Newcastle disease virus Clone30 by selecting sensitive tumor host and constructing more oncolytic viruses

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.

Newcastle Disease Virus at the Forefront of Cancer Immunotherapy

“…Tumor cell susceptibility to NDV infection may also be based on the presence of sialic acid-containing cell surface proteins. It was proposed that the combination of altered type I IFN-related gene expression and sialic acid content could act as a clinical biomarker for determining susceptible tumor types [24]. Finally, defects in apoptotic pathways such as the Fas-FasL interaction or overexpression of antiapoptotic genes such as Livin and BcL-xL, which are documented in many tumor types, may increase susceptibility to NDV allowing for viral persistence, increased replication, and spread to surrounding cells [25][26][27].…”

Viral Proteins as Emerging Cancer Therapeutics

“…NDV binds to the sialic acid (Sia) receptor on host cells and, therefore, can infect a broad range of cell types. Different receptor isoform expression patterns between cell types contribute to the selection of cancer cells like HeLa by NDV over normal cells like BHK fibroblasts [ 91 , 92 ]. NDV can achieve oncolysis via activation of the extrinsic or intrinsic apoptosis, activation of PERK kinase followed by caspase-12, and secretion of cytokines like tumor necrosis factor–α (TNF-α) amongst various others, from the infected tumor cells [ 93 ].…”

“…The F protein from NDV is a class I viral membrane fusion protein present as a trimer in the virion where the cleavage site of the F protein is known to be responsible for virulence and the formation of syncytia [ 92 ]. Both Fusion (F) and Hemaglutinin-Neuraminidase (HN) proteins expressed on the surface have been studied to interact and fuse with host cellular membranes.…”

“…This, in turn, modulates tumor cell surface markers and induces downstream apoptosis [ 93 ]. However, Liu et al [ 92 ] lately reported that that the F protein plays a major role in NDV-induced oncolytic effect on xenograftic mice from H22 and 4T1 cell lines, possibly via mtorc1 inhibition but it remains to be confirmed in further studies. Like ARV p17, NDV F protein is also postulated to induce autophagy by upregulating autophagy related 5 (ATG5), beclin-1, and microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B) like markers.…”

“…Furthermore, Sindbis viral vectors have been produced by co-electroporation of in vitro-transcribed RNAs from replicon (replicase and viral subgenomic promoter sequences) and helper plasmids (viral subgenomic promoter, capsid, and envelope protein sequences) to administer nsp2 and E1/E2 proteins, respectively ( Figure 5 ) to minimize collateral effects in vitro whereas intraperitoneal injection of SCID mice with Sindbis vectors (~10 6 TU) resulted to be a successful therapy in vivo [ 112 ]. Similarly, NDV chimeric rClone30 vectors were designed by recombination of Clone30 lentogenic strain with F and HN genes from Anhinga mesogenic strain to achieve desired oncolytic activity in the absence of hazardous consequences associated with virulent velogenic strains [ 92 ].…”