Vesicular stomatitis virus inhibits mitotic progression and triggers cell death

Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
EMBO Reports (Impact Factor: 9.06). 10/2009; 10(10):1154-60. DOI: 10.1038/embor.2009.179
Source: PubMed


Vesicular stomatitis virus (VSV) infects and kills a wide range of cell types; however, the mechanisms involved in VSV-mediated cell death are not fully understood. Here we show that VSV infection interferes with mitotic progression, resulting in cell death. This effect requires the interaction of VSV matrix (M) protein with the Rae1-Nup98 complex in mitosis, which is associated with a subset of ribonucleoproteins (RNPs). VSV displaced Rae1 from spindle poles, caused spindle abnormalities and triggered substantial cell death during metaphase. These effects were attenuated in cells infected with VSV expressing a mutant M protein that does not bind efficiently to the Rae1-Nup98-RNP complex. In cells that progressed to late mitosis, M protein prevented proper nuclear formation and chromatin decondensation. VSV is an oncolytic (anti-tumour) agent as it preferentially replicates and kills tumour cells. As tumour cells have a high mitotic index, VSV-mediated mitotic cell death probably contributes to its oncolytic activity.

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Available from: Jen-Hsuan Wei
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    • "VSV M mutants with defects in Rae1–Nup98 binding are unable to inhibit mRNA nuclear export (Faria et al., 2005). Interestingly, a study by Chakraborty et al. (2009) showed that interaction of the VSV M protein with the Rae1– Nup98 complex during mitosis causes spindle abnormalities and triggers cell death during metaphase. The M protein may also inhibit host gene expression via inhibition of cellular mRNA synthesis (Yuan et al., 2001). "
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    ABSTRACT: Oncolytic virus (OV) therapy is an emerging anti-cancer approach that utilizes viruses to preferentially infect and kill cancer cells, while not harming healthy cells. Vesicular stomatitis virus (VSV) is a prototypic non-segmented, negative-strand RNA virus with inherent OV qualities. Antiviral responses induced by type I interferon pathways are believed to be impaired in most cancer cells, making them more susceptible to VSV than normal cells. Several other factors make VSV a promising OV candidate for clinical use, including its well-studied biology, a small, easily manipulated genome, relative independence of a receptor or cell cycle, cytoplasmic replication without risk of host-cell transformation, and lack of pre-existing immunity in humans. Moreover, various VSV-based recombinant viruses have been engineered via reverse genetics to improve oncoselectivity, safety, oncotoxicity and stimulation of tumour-specific immunity. Alternative delivery methods are also being studied to minimize premature immune clearance of VSV. OV treatment as a monotherapy is being explored, although many studies have employed VSV in combination with radiotherapy, chemotherapy or other OVs. Preclinical studies with various cancers have demonstrated that VSV is a promising OV; as a result, a human clinical trial using VSV is currently in progress.
    Full-text · Article · Oct 2012 · Journal of General Virology
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    • "The robust production of VSV proteins in cancer cells likely leads to the killing of the malignant cells. M protein produced in cancer cells can bind the nuclear pore, suppress cell cycle progression[101], and induce apoptosis[42],[102]. Moreover, the released VSV particles can then infect and kill adjacent cancer cells in the tumor, leading to additional activation of host immune response for tumor elimination. "
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    ABSTRACT: In the last decade, we have gained significant understanding of the mechanism by which vesicular stomatitis virus (VSV) specifically kills cancer cells. Dysregulation of translation and defective innate immunity are both thought to contribute to VSV oncolysis. Safety and efficacy are important objectives to consider in evaluating VSV as a therapy for malignant disease. Ongoing efforts may enable VSV virotherapy to be considered in the near future to treat drug-resistant ovarian cancer when other options have been exhausted. In this article, we review the development of VSV as a potential therapeutic approach for recurrent or drug-resistant ovarian cancer.
    Full-text · Article · Nov 2011 · Chinese journal of cancer
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    • "Based on this observation, we hypothesized that the acquisition of proliferating activity and, therefore, increased protein translation activity, might favor VSV permissiveness, as reported in primary T-lymphocytes [10]. Moreover, a recent publication indicates that disruption of cell cycle in normal rat kidney cells (NRK) is important for VSV ability to kill cells [36]. Chakraborty and colleagues report that VSV infection in NRK cells results in significant cell death during metaphase. "
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    ABSTRACT: The intrinsic oncolytic specificity of vesicular stomatitis virus (VSV) is currently being exploited to develop alternative therapeutic strategies for hepatocellular carcinoma (HCC). Identifying key regulators in diverse transduction pathways that define VSV oncolysis in cancer cells represents a fundamental prerequisite to engineering more effective oncolytic viral vectors and adjusting combination therapies. After having identified defects in the signalling cascade of type I interferon induction, responsible for attenuated antiviral responses in human HCC cell lines, we have now investigated the role of cell proliferation and translation initiation. Cell cycle progression and translation initiation factors eIF4E and eIF2Bepsilon have been recently identified as key regulators of VSV permissiveness in T-lymphocytes and immortalized mouse embryonic fibroblasts, respectively. Here, we show that in HCC, decrease of cell proliferation by cell cycle inhibitors or siRNA-mediated reduction of G(1) cyclin-dependent kinase activities (CDK4) or cyclin D1 protein expression, do not significantly alter viral growth. Additionally, we demonstrate that translation initiation factors eIF4E and eIF2Bepsilon are negligible in sustaining VSV replication in HCC. Taken together, these results indicate that cellular proliferation and the initiation phase of cellular protein synthesis are not essential for successful VSV oncolysis of HCC. Moreover, our observations indicate the importance of cell-type specificity for VSV oncolysis, an important aspect to be considered in virotherapy applications in the future.
    Full-text · Article · Jun 2010 · PLoS ONE
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