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Enhanced cytotoxicity of reovirus and radiotherapy in melanoma cells is mediated through increased viral replication and mitochondrial apoptotic signalling.

ABSTRACT: Oncolytic viruses selectively target and replicate in cancer cells, providing us with a unique tool with which to target and kill tumour cells. These viruses come from a diverse range of viral families including reovirus type 3 Dearing (RT3D), a non-pathogenic human double-stranded RNA oncolytic virus, which has been shown to be an effective therapeutic agent, both as a mono-therapy and in combination with traditional chemotherapeutic drugs. This study investigated the interaction between RT3D and radiotherapy in melanoma cell lines with a BRAF mutant, Ras mutant or BRAF/Ras wild type genotype. The data indicates that RT3D combined with radiotherapy significantly increased cytotoxicity relative to either single agent, independent of genotype, both in vitro and in vivo. The mechanism of enhanced cytotoxicity was dependent on an increase in viral replication, mediated by CUG2 up-regulation and subsequent down-regulation of pPKR and p-eIF2?, leading to the activation of mitochondrial apoptotic signalling resulting in increased cell death.

SUBMITTER: McEntee G

PROVIDER: S-EPMC5217035 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Enhanced cytotoxicity of reovirus and radiotherapy in melanoma cells is mediated through increased viral replication and mitochondrial apoptotic signalling.

McEntee Gráinne G Kyula Joan N JN Mansfield David D Smith Henry H Wilkinson Michelle M Gregory Claire C Roulstone Victoria V Coffey Matt M Harrington Kevin J KJ

Oncotarget 20160701 30

Oncolytic viruses selectively target and replicate in cancer cells, providing us with a unique tool with which to target and kill tumour cells. These viruses come from a diverse range of viral families including reovirus type 3 Dearing (RT3D), a non-pathogenic human double-stranded RNA oncolytic virus, which has been shown to be an effective therapeutic agent, both as a mono-therapy and in combination with traditional chemotherapeutic drugs. This study investigated the interaction between RT3D a ...[more]

PMID: 27384486

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Project description:Reovirus serotype 3 Dearing (T3D) replicates preferentially in transformed cells and is in clinical trials as a cancer therapy. Laboratory strains of T3D, however, exhibit differences in plaque size on cancer cells and differences in oncolytic activity in vivo This study aimed to determine why the most oncolytic T3D reovirus lab strain, the Patrick Lee laboratory strain (T3DPL), replicates more efficiently in cancer cells than other commonly used laboratory strains, the Kevin Coombs laboratory strain (T3DKC) and Terence Dermody laboratory (T3DTD) strain. In single-step growth curves, T3DPL titers increased at higher rates and produced ∼9-fold higher burst size. Furthermore, the number of reovirus antigen-positive cells increased more rapidly for T3DPL than for T3DTD In conclusion, the most oncolytic T3DPL possesses replication advantages in a single round of infection. Two specific mechanisms for enhanced infection by T3DPL were identified. First, T3DPL exhibited higher cell attachment, which was attributed to a higher proportion of virus particles with insufficient (≤3) σ1 cell attachment proteins. Second, T3DPL transcribed RNA at rates superior to those of the less oncolytic T3D strains, which is attributed to polymorphisms in M1-encoding μ2 protein, as confirmed in an in vitro transcription assay, and which thus demonstrates that T3DPL has an inherent transcription advantage that is cell type independent. Accordingly, T3DPL established rapid onset of viral RNA and protein synthesis, leading to more rapid kinetics of progeny virus production, larger virus burst size, and higher levels of cell death. Together, these results emphasize the importance of paying close attention to genomic divergence between virus laboratory strains and, mechanistically, reveal the importance of the rapid onset of infection for reovirus oncolysis.IMPORTANCE Reovirus serotype 3 Dearing (T3D) is in clinical trials for cancer therapy. Recently, it was discovered that highly related laboratory strains of T3D exhibit large differences in their abilities to replicate in cancer cells in vitro, which correlates with oncolytic activity in a murine model of melanoma. The current study reveals two mechanisms for the enhanced efficiency of T3DPL in cancer cells. Due to polymorphisms in two viral genes, within the first round of reovirus infection, T3DPL binds to cells more efficiency and more rapidly produces viral RNAs; this increased rate of infection relative to that of the less oncolytic strains gives T3DPL a strong inherent advantage that culminates in higher virus production, more cell death, and higher virus spread.

Dataset Information

Enhanced cytotoxicity of reovirus and radiotherapy in melanoma cells is mediated through increased viral replication and mitochondrial apoptotic signalling.

Publications

Enhanced cytotoxicity of reovirus and radiotherapy in melanoma cells is mediated through increased viral replication and mitochondrial apoptotic signalling.

Similar Datasets

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