Oncogenic Ras Promotes Reovirus Spread by Suppressing IFN-β Production through Negative Regulation of <i>RIG-I</i> Signaling

Shmulevitz, Maya; Pan, Lu-Zhe; Garant, Katy; Pan, Da; Lee, Patrick W.K.

doi:10.1158/0008-5472.can-09-4676

Cited by 92 publications

(115 citation statements)

References 27 publications

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“…However, in RAS-negative fibroblasts, all reovirus subtypes did not show oncolytic activity. These observations are in accordance with previous studies (5,10,11,(14)(15)(16).…”

Section: Discussionsupporting

confidence: 94%

All reovirus subtypes show oncolytic potential in primary cells of human high-grade glioma

Alloussi

Alkassar²,

Urbschat³

et al. 2011

Oncol Rep

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Abstract. Reoviridae are non-human pathogenic viruses. The family of reoviridae consists of 4 different subtypes. Many studies have proven that the Dearing subtype 3 has oncolytic potential. This potential is related to the RAS protein expression in tumour cells. The aim of this study, was to investigate whether all reovirus subtypes have oncolytic potential and whether there are differences in their efficacy, in particular for high-grade glioma. To evaluate the oncolytic potential, we performed an in vitro head-to-head study for all reovirus subtypes in 5 primary cell cultures of high-grade gliomas. The oncolytic activity was determined using end-point titration with observation of the cytopathogenic effect. For measurement of RAS activity, we performed an immunofluorescent detection stain on all cell cultures. For quantification of the virus, an RT-PCR measurement for all subtypes was performed. All reovirus subtypes showed oncolytic activity in the observed glioma biopsies. These observations correlated with RAS overexpression in the observed cells. All glioma biopsies overexpressed the RAS protein. The quantitative oncolytic potential differed in relation to the single observed cell culture and in relation to the chosen reovirus subtype. To our knowledge, this is the first study showing oncolytic activity for all reovirus subtypes. We show the relationship and correlation between RAS protein overexpression and vulnerability of cells to reovirus. Efficacy of the different subtypes is interindividually different and cannot be forecast.

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“…However, in RAS-negative fibroblasts, all reovirus subtypes did not show oncolytic activity. These observations are in accordance with previous studies (5,10,11,(14)(15)(16).…”

Section: Discussionsupporting

confidence: 94%

All reovirus subtypes show oncolytic potential in primary cells of human high-grade glioma

Alloussi

Alkassar²,

Urbschat³

et al. 2011

Oncol Rep

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“…Consistent with prior reports, reovirus exposure induces an IFN-b response (Hamamdzic et al, 2001;Holm et al, 2007;Steele et al, 2011). While IFN production has been reported to decrease viral spread and efficacy, IFNs have also been shown to elicit anti-tumor effects via inhibition of angiogenesis and stimulation of apoptosis (Sidky and Borden, 1987;Taylor et al, 2008;Shmulevitz et al, 2010). To investigate whether IFN-b contributes to Reolysin-mediated apoptosis, we blocked its activity with neutralizing antibody.…”

Section: Resultssupporting

confidence: 70%

“…Our initial gene expression profiling experiment demonstrated that Reolysin treatment induced a strong IFN-b response. This is not surprising given that previous studies have demonstrated that this antiviral response may limit reovirus replication in nontransformed cells (Rudd and Lemay, 2005;Shmulevitz et al, 2010). However, it is also possible that IFN stimulation may contribute to Reolysin's anti-tumor activity (Taylor et al, 2008).…”

Section: Discussionmentioning

confidence: 79%

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

et al. 2011

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Oncolytic virotherapy with reovirus has demonstrated anti-cancer activity and minimal toxicity in clinical trials, but the mechanisms underlying these effects have not been fully elucidated. Reolysin, a proprietary formulation of reovirus for cancer therapy, stimulated selective viral replication and apoptosis in multiple myeloma (MM) cells. Reolysin-mediated apoptosis was associated with an induction of endoplasmic reticular (ER) stress-related gene expression, swelling of the endoplasmic reticulum, increases in intracellular calcium levels and a strong induction of the Bcl-2 homology 3 (BH3)-only pro-apoptotic protein NOXA. Knockdown of NOXA expression by short hairpin RNA significantly reduced the pro-apoptotic effects of Reolysin. We next showed that co-administration of Reolysin and bortezomib resulted in the dual accumulation of viral and ubiquitinated proteins, which led to enhanced ER stress, NOXA induction and apoptosis. Importantly, the combination of reovirus infection and proteasomal inhibition significantly decreased tumor burden in a xenograft and syngeneic bone disease model of MM without exhibiting adverse side effects. Our study establishes ER stress stimulation and NOXA induction as novel mediators of reovirus-induced apoptosis. Furthermore, reovirus infection can be used as a promising approach to augment the anti-myeloma activity of bortezomib by promoting additional stress to the endoplasmic reticulum of MM cells.

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“…Mammalian reovirus (type 3 Dearing) and RSV (serotype A, Long strain) were propagated, purified, and UV‐inactivated as previously described 28, 31, 32. UV inactivation was confirmed by standard plaque assay and flow cytometric analysis of virus treated cells.…”

Section: Methodsmentioning

confidence: 99%

Interferon α2 and interferon γ induce the degranulation independent production of VEGF‐A and IL‐1 receptor antagonist and other mediators from human mast cells

Oldford

Salsman

Portales‐Cervantes

et al. 2017

Immunity Inflam & Disease

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BackgroundMast cells are resident immune effector cells, often studied in the context of allergic disease. Found in substantial numbers at sites of potential infection they are increased at sites of angiogenesis and can be pivotal for the sensing and clearance of a variety of pathogens. Interferons (IFNs) are cytokines that are critical for host defence against intracellular pathogens. Increased levels of IFNs are observed during viral infection and in autoimmune diseases. IFNs are also widely used therapeutically and have been examined in the therapy of severe asthma.ObjectiveTo define the selective human mast cell cytokine and chemokine response following activation with type I or type II IFN's.MethodsThe ability of both IFNα2 and IFNγ to induce cytokine production by human cord blood‐derived mast cells was examined in vitro. Cytokine and chemokine production at 6 and 24 h was assessed by multiplex protein analysis. Degranulation was assessed by β‐hexosaminidase release. Mast cells were also treated with reovirus or respiratory syncytial virus and their production of CXCL10, IL‐1 receptor antagonist (IL‐1Ra), and vascular endothelial growth factor (VEGF) examined after 24 h.ResultsIn addition to increased expression of classical IFN response genes, such as CXCL10, small but significant increases in CCL5 and IL‐17 production were observed following IFN activation. Notably, human mast cells produced both VEGF and IL‐1Ra in a dose dependent manner. These responses occurred in the absence of mast cell degranulation by a mechanism consistent with classical IFN signaling. Both reovirus and respiratory syncytial virus infection of mast cells, were also associated with IFN‐dependent IL‐1Ra expression.Conclusion and Clinical RelevanceOur findings demonstrate that IFNs have profound impact on cytokine and chemokine expression by human mast cells, alone or in the context of viral infection. Mast cell VEGF and IL‐1Ra responses to IFNs could impact the regulation of local inflammatory responses and subsequent tissue remodeling.

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Oncogenic Ras Promotes Reovirus Spread by Suppressing IFN-β Production through Negative Regulation of RIG-I Signaling

Cited by 92 publications

References 27 publications

All reovirus subtypes show oncolytic potential in primary cells of human high-grade glioma

All reovirus subtypes show oncolytic potential in primary cells of human high-grade glioma

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

Interferon α2 and interferon γ induce the degranulation independent production of VEGF‐A and IL‐1 receptor antagonist and other mediators from human mast cells

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