Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity

Cancer Cell. 2004 Dec;6(6):611-23. doi: 10.1016/j.ccr.2004.11.012.

Abstract

ONYX-015 is an adenovirus that lacks the E1B-55K gene product for p53 degradation. Thus, ONYX-015 was conceived as an oncolytic virus that would selectively replicate in p53-defective tumor cells. Here we show that loss of E1B-55K leads to the induction, but not the activation, of p53 in ONYX-015-infected primary cells. We use a novel adenovirus mutant, ONYX-053, to demonstrate that loss of E1B-55K-mediated late viral RNA export, rather than p53 degradation, restricts ONYX-015 replication in primary cells. In contrast, we show that tumor cells that support ONYX-015 replication provide the RNA export function of E1B-55K. These data reveal that tumor cells have altered mechanisms for RNA export and resolve the controversial role of p53 in governing ONYX-015 oncolytic selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics*
  • Adenoviridae / metabolism
  • Adenovirus E1A Proteins / genetics
  • Adenovirus E1A Proteins / metabolism
  • Adenovirus E1B Proteins / genetics
  • Adenovirus E1B Proteins / metabolism
  • Adenoviruses, Human / genetics
  • Adenoviruses, Human / metabolism
  • Apoptosis
  • Blotting, Western
  • Capsid Proteins / genetics
  • Capsid Proteins / metabolism
  • Caspase 3
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cytopathogenic Effect, Viral / genetics
  • DNA, Viral / biosynthesis
  • Epithelial Cells / metabolism
  • Epithelial Cells / radiation effects
  • Epithelial Cells / virology
  • Gene Expression / genetics
  • HCT116 Cells
  • Humans
  • In Situ Hybridization, Fluorescence
  • Models, Biological
  • Mutation
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / virology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism
  • Polymerase Chain Reaction
  • Protein Biosynthesis / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-mdm2
  • RNA Transport
  • RNA, Viral / metabolism*
  • Tumor Suppressor Protein p14ARF / metabolism
  • Tumor Suppressor Protein p53 / metabolism*
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism
  • Viral Plaque Assay
  • Viral Proteins / metabolism
  • Viral Vaccines
  • Virus Replication / genetics*
  • bcl-2-Associated X Protein

Substances

  • Adenovirus E1A Proteins
  • Adenovirus E1B Proteins
  • CDKN1A protein, human
  • Capsid Proteins
  • Caspase Inhibitors
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • DNA, Viral
  • L4-100K protein, adenovirus type 5
  • Nuclear Proteins
  • ONYX015
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Viral
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • Viral Nonstructural Proteins
  • Viral Proteins
  • Viral Vaccines
  • bcl-2-Associated X Protein
  • hexon capsid protein, Adenovirus
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Poly(ADP-ribose) Polymerases
  • CASP3 protein, human
  • Caspase 3
  • Caspases