The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus

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

“…However, inhibition of Src kinase activity does not affect reoviral replication (Figure 3b). Although several lines of evidence indicate that Ras-transformed cells are preferentially susceptible to reovirus through the inactivation of PKR phosphorylation, 2,8 we have recently found that PKR inactivation by Ras activation does not determine reovirus replication in a liver cell expressing hepatitis B virus X, an oncoprotein of the hepatitis B virus. 29 Therefore, we believe that other factors mediated by CUG2 may be involved in reovirus replication.…”

“…[3][4][5] However, the reovirus shows dramatic cytolytic activity in certain types of transformed cells. 6,7 There is a strong body of evidence that Ras-transformed cells are preferentially susceptible to reovirus (type 3 Dearing strain) through inactivation of PKR (dsRNAactivated protein kinase) phosphorylation, 8,9 and activation of the oncogenic Ras-signaling pathway enhances reoviral oncolytic targeting in various types of human cancers, 10,11 although our recent study shows that other signaling pathways may also contribute to the susceptibility of a hepatic cancer cell to reoviral replication and oncolysis. 12 Reoviral efficacy has been examined in the treatment of gliomas and other cancers in immunocompetent hosts and has not been shown to produce significant toxicities.…”

PKR; a sentinel kinase for cellular stress

“…In PKR null cells, PDGF-induced DNA binding activity and serine 727 phosphorylation of Stat3 is de®cient and the induction of c-fos defective. In ras transformed cells an inhibitor is present which blocks the activity of PKR activity, indicating that events upstream of ras contribute to PKR-dependent signaling (Strong et al, 1998). Since oncogenic ras can activate NF-kB through a p38 or related stress activated kinase pathway and signals from an oncogenic ras pathway block PKR, then it follows that PKR should not be able to contribute to the activation of NF-kB in transformed ®broblasts.…”

Clinical development directions in oncolytic viral therapy

“…[136][137][138] Importantly, reovirus type 3 Dearing strain exhibits replication in cells with an activated Ras signaling pathway, a significant finding because of the link between oncogenesis and mutations in the ras gene and pathway, and it has been demonstrated that this is due to inhibition of double-stranded RNA-activated protein kinase resulting in cell lysis. 139,140 Although normal mouse fibroblast cells (NIH3T3) do not normally support reovirus replication, NIH3T3 cells transformed with activated ras, epidermal growth factor receptor or V-erb B oncogene (for example, activated ras pathway elements) are lysed by uninhibited reovirus replication. It is now understood that an activated ras pathway, which is present in many ovarian, breast, colon and lung cancers, prevents viralinduced PKR activation and subsequent EIF-2 a-phosphorylation, potentiating cellular protein production and viral replication.…”