Oncogenes: The Passport for Viral Oncolysis through PKR Inhibition

Abstract

The transforming properties of oncogenes are derived from gain-of-function mutations, shifting cell signaling from highly regulated homeostatic to an uncontrolled oncogenic state, with the contribution of the inactivating mutations in tumor suppressor genes P53 and RB, leading to tumor resistance to conventional and target-directed therapy. On the other hand, this scenario fulfills two requirements for oncolytic virus infection in tumor cells: inactivation of tumor suppressors and presence of oncoproteins, also the requirements to engage malignancy. Several of these oncogenes have a negative impact on the main interferon antiviral defense, the double-stranded RNA-activated protein kinase (PKR), which helps viruses to spontaneously target tumor cells instead of normal cells. This review is focused on the negative impact of overexpression of oncogenes on conventional and targeted therapy and their positive impact on viral oncolysis due to their ability to inhibit PKR-induced translation blockage, allowing virion release and cell death.

Oncolytic Viruses as Antigen-Agnostic Cancer Vaccines

“…In parallel with the targeted suppression of host cell protein synthesis by the invading virus, one of the key defensive strategies of a virus-infected host cell is to globally suppress its own macromolecular synthetic machinery thereby interfering with virus progeny production. This is most notably achieved through phosphorylation of the Met-tRNA f -binding factor eIF2α by the interferon-inducible, double-stranded RNA (dsRNA)-activated protein PKR (Fernandes, 2016; Gale and Katze, 1998). Not surprisingly, virally encoded proteins often interfere with this pathway, for example via the HSV-1 encoded protein ICP34.5 which recruits protein phosphatase 1 (PP1) to dephosphorylate eIF2α (Mohr, 2004).…”

Role of MAPK/MNK1 signaling in virus replication

“…It has three sensor units viz; (i) general control nonrepressed 2 (GCN2) that is activated in response to amino-acid deprivation (ii) PKR-like endoplasmic reticulum kinase (PERK) that is activated in response to overloaded or misfolded proteins in the endoplasmic reticulum and (iii) heme-regulated eIF2α kinase (HRI) that is activated in response to reduced heme levels as well as heat shock (Dang Do et al, 2009). Activated PKR phosphorylates α subunit of eIF2-α as well as activating stress pathways-JNK, p38, NFκB (Fernandes, 2016) and protein phosphatase 2 A (PP2 A) (Ahn et al, 2007).…”

Current understanding of reovirus oncolysis mechanisms

“…Activated Ras inhibits PKR activity through a variety of mechanisms, thereby preventing PKR-mediated inhibition of host protein synthesis. 69 PKR activity is not detected in reovirus-infected Ras-transformed cells and viral protein synthesis is increased relative to untransformed cells. 70 Moreover, pharmacological treatment of untransformed cells with a PKR inhibitor enhances reovirus gene expression.…”