title: An unexpected inhibition of antiviral signaling by virus-encoded tumor suppressor p53 in pancreatic cancer cells.
abstract: Virus-encoded tumor suppressor p53 transgene expression has been successfully used in vesicular stomatitis virus (VSV) and other oncolytic viruses (OVs) to enhance their anticancer activities. However, p53 is also known to inhibit virus replication via enhanced type I interferon (IFN) antiviral responses. To examine whether p53 transgenes enhance antiviral signaling in human pancreatic ductal adenocarcinoma (PDAC) cells, we engineered novel VSV recombinants encoding human p53 or the previously described chimeric p53-CC, which contains the coiled-coil (CC) domain from breakpoint cluster region (BCR) protein and evades the dominant-negative activities of endogenously expressed mutant p53. Contrary to an expected enhancement of antiviral signaling by p53, our global analysis of gene expression in PDAC cells showed that both p53 and p53-CC dramatically inhibited type I IFN responses. Our data suggest that this occurs through p53-mediated inhibition of the NF-κB pathway. Importantly, VSV-encoded p53 or p53-CC did not inhibit antiviral signaling in non-malignant human pancreatic ductal cells, which retained their resistance to all tested VSV recombinants. To the best of our knowledge, this is the first report of p53-mediated inhibition of antiviral signaling, and it suggests that OV-encoded p53 can simultaneously produce anticancer activities while assisting, rather than inhibiting, virus replication in cancer cells.
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Hastie
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA.
authors.forename: Marcela
authors.initials: M
authors.lastname: Cataldi
authors.affiliation: Cannon Research Center, Carolinas Healthcare System, Charlotte, NC, USA.
authors.forename: Nury
authors.initials: N
authors.lastname: Steuerwald
authors.affiliation: Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC, USA. Electronic address: vzgrdzel@uncc.edu.
authors.forename: Valery Z
authors.initials: VZ
authors.lastname: Grdzelishvili
mesh_terms: D045744:Cell Line, Tumor; D054884:Host-Pathogen Interactions; D006801:Humans; D007370:Interferon Type I / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D018116:Vesiculovirus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D007370:Interferon Type I; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins
keywords: Anticancer; Antiviral signaling; Gene therapy; Oncolytic; Pancreatic cancer; Tumor suppressor; Type I interferon; VSV; Vesicular stomatitis virus; p53