Connecting Reovirus Oncolysis and Ras Signaling

Marcato, Paola; Shmulevitz, Maya; Lee, Patrick W.

doi:10.4161/cc.4.4.1600

Cited by 40 publications

(28 citation statements)

References 41 publications

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“…8,9,44 The detailed relationship between the cell's Ras status and the various consequences of infection has not been fully elucidated yet. 5,44 While our data suggests components of the Ras/ RalGEF/p38 pathway 6 (particularly p38 and in some cell lines PI3K, but not MEK 1/2) are implicated in the reovirus-induced killing of melanoma (Figure 4), for clinical application the key findings of this study are the sensitivity of melanoma (both cell lines and primary tumours) to reovirus killing and replication, together with the relative resistance of Melan-A normal melanocytes. Sequencing to date of our lines has shown that they are all mutant in the Ras/BRAF pathway (as expected for melanomas 45 ), while Melan-A is normal.…”

Section: Discussionmentioning

confidence: 97%

“…Since permissive reovirus replication is also a feature of cells with defects in pathways lying up or downstream of the Ras proteins themselves, this implicates a significant proportion of human tumours as potentially susceptible to reoviral oncolysis. 4,5 More recent studies have suggested that the determinants of susceptibility to reovirus-induced cell death may be more complex than simple generic activation of the Ras signalling pathway. Norman et al 6 reported that the activity of the Ras/RalGEF/p38 pathway is the major determinant of susceptibility in transformed NIH 3T3 cells; other work has suggested that Ras activation status does not affect reovirus replication in C26 murine colorectal cancer cells, but does influence their sensitivity to reovirus-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

et al. 2008

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Reovirus is a promising unmodified double-stranded RNA (dsRNA) anti-cancer oncolytic virus, which is thought to specifically target cells with activated Ras. Although reovirus has been tested in a wide range of preclinical models and has entered early clinical trials, it has not previously been tested for the treatment of human melanoma. Here, we show that reovirus effectively kills and replicates in both human melanoma cell lines and freshly resected tumour; intratumoural injection also causes regression of melanoma in a xenograft in vivo model. Reovirus-induced melanoma death is blocked by caspase inhibition and is dependent on constituents of the Ras/RalGEF/p38 pathway. Reovirus melanoma killing is more potent than, and distinct from, chemotherapy or radiotherapy-induced cell death; a range of inflammatory cytokines and chemokines are released by infected tumour cells, while IL-10 secretion is abrogated. Furthermore, the inflammatory response generated by reovirus-infected tumour cells causes bystander toxicity against reovirus-resistant tumour cells and activates human myeloid dendritic cells (DC) in vitro. Hence, reovirus is suitable for clinical testing in melanoma, and may provide a useful danger signal to reverse the immunologically suppressive environment characteristic of this tumour.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

et al. 2008

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“…We are now conducting further studies to identify a binding protein against CUG2 to resolve this question. Moreover, as ERK activity has been reported not to be involved in reoviral replication, 2,28 we only need to focus on Src kinase. However, inhibition of Src kinase activity does not affect reoviral replication (Figure 3b).…”

Section: Discussionmentioning

confidence: 99%

CUG2, a novel oncogene confers reoviral replication through Ras and p38 signaling pathway

Park

I-R

et al. 2010

Cancer Gene Ther

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As we have recently found a novel oncogene, the cancer-upregulated gene 2 (CUG2), which was elevated in a variety of tumor tissues such as the ovary, liver, lung and pancreas, we examined whether reovirus could efficiently induce cytolysis in cancer cells expressing CUG2 and thus be used as a potential cancer therapeutic agent. In this study, we describe experiments in which we use reovirus to treat NIH3T3 cells stably expressing either CUG2 (NIH-CUG2) or vector only (NIH-Vec). NIH-CUG2 cells readily support reoviral proliferation and undergo apoptosis, whereas NIH-Vec cells are highly resistant to reoviral infection and virusinduced apoptosis. This notable result may be explained by the observation that CUG2 expression inhibits PKR activation, leading to reoviral proliferation in nonpermissive NIH3T3 cells. Furthermore, reovirus infection results in almost complete regression of tumorgenic NIH-CUG2 cells in transplanted nude mice. As we found that CUG2 enhances activation of MAPK (ERK, JNK and p38), Src kinase and Ras, we examined whether CUG2 confers reoviral replication independent of the Ras or p38 MAPK signaling pathway. From these experiments we found that either inhibition of p38 MAPK or Ras blocks reoviral proliferation even in the presence of CUG2 but inhibition of ERK, JNK and Src kinase does not, indicating that activation of p38 MAPK and Ras has critical roles in reoviral replication in CUG2-expressing tumor cells. Accordingly, we propose that reovirus can be useful in the treatment of transformed cells expressing CUG2, which is commonly detected in various tumor tissues.

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“…Early studies proposed a model in which mutations in Ras inhibit antiviral protein kinase R (PKR) signaling and activate other signal transduction pathways to promote viral protein synthesis and apoptosis in reovirus-infected transformed cells (76). More recent work from our laboratory and others revealed that efficient cell entry of reovirus particles into transformed cells is a major determinant of its oncolytic potential (2,47,71).…”

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confidence: 99%

Reovirus Uses Multiple Endocytic Pathways for Cell Entry

Schulz

Haj

Schiff

2012

J Virol

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Entry of reovirus virions has been well studied in several tissue culture systems. After attachment to junctional adhesion molecule A (JAM-A), virions undergo clathrin-mediated endocytosis followed by proteolytic disassembly of the capsid and penetration to the cytoplasm. However, during in vivo infection of the intestinal tract, and likely in the tumor microenvironment, capsid proteolysis (uncoating) is initiated extracellularly. We used multiple approaches to determine if uncoated reovirus particles, called intermediate subviral particles (ISVPs), enter cells by directly penetrating the limiting membrane or if they take advantage of endocytic pathways to establish productive infection. We found that entry and infection by reovirus ISVPs was inhibited by dynasore, an inhibitor of dynamin-dependent endocytosis, as well as by genistein and dominant-negative caveolin-1, which block caveolar endocytosis. Inhibition of caveolar endocytosis also reduced infection by reovirus virions. Extraction of membrane cholesterol with methyl-␤-cyclodextrin inhibited infection by virions but had no effect when infection was initiated with ISVPs. We found this pathway to be independent of both clathrin and caveolin. Together, these data suggest that reovirus virions can use both dynamin-dependent and dynamin-independent endocytic pathways during cell entry, and they reveal that reovirus ISVPs can take advantage of caveolar endocytosis to establish productive infection.

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Connecting Reovirus Oncolysis and Ras Signaling

Cited by 40 publications

References 41 publications

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma

CUG2, a novel oncogene confers reoviral replication through Ras and p38 signaling pathway

Reovirus Uses Multiple Endocytic Pathways for Cell Entry

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