title: Oncogenes in Ras signalling pathway dictate host-cell permissiveness to herpes simplex virus 1.
abstract: The importance of herpes simplex viruses (HSV) as human pathogens and the emerging prospect of using mutant derivatives of HSV-1 as potential anti-cancer therapeutics have necessitated a thorough investigation into the molecular basis of host-cell permissiveness to HSV. Here we show that NIH-3T3 cells transformed with the oncogenes v-erbB, activated sos or activated ras become significantly more permissive to HSV-1. Inhibitors of the Ras signalling pathway, such as farnesyl transferase inhibitor 1 and PD98059, effectively suppressed HSV-1 infection of ras-transformed cells. Enhanced permissiveness of the transformed cells was linked to the inhibition of virus-induced activation (phosphorylation) of the double-stranded RNA-activated protein kinase (PKR), thereby allowing viral transcripts to be translated in these cells. An HSV-1-derived oncolytic mutant, R3616, was also found to infect preferentially both transformed cells and PKR-/- (but not PKR+/+) mouse embryo fibroblasts. These observations suggest that HSV-1 specifically targets cells with an activated Ras signalling pathway, and have important ramifications in the use of engineered HSV in cancer therapy, the development of strategies against HSV infections, and the controversial role of HSV in human cancers.
authors.affiliation: Cancer Biology Research Group, and Department of Microbiology and Infectious Diseases, University of Calgary Health Sciences Center, Calgary, Alberta T2N 4N1, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Farassati
authors.forename: A D
authors.initials: AD
authors.lastname: Yang
authors.forename: P W
authors.initials: PW
authors.lastname: Lee
mesh_terms: D016475:3T3 Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D002461:Cell Line, Transformed / Q000166:cytology / Q000378:metabolism / Q000821:virology; D002472:Cell Transformation, Viral / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D005419:Flavonoids / Q000494:pharmacology; D018773:Genes, erbB-1 / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006790:Host-Parasite Interactions / Q000235:genetics*; D048369:MAP Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D009857:Oncogenes / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D020839:Son of Sevenless Protein, Drosophila / Q000235:genetics; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019883:Alkyl and Aryl Transferases; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D005419:Flavonoids; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D020839:Son of Sevenless Protein, Drosophila; D014764:Viral Proteins; D019892:eIF-2 Kinase; D018631:ras Proteins; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one