Characterization of the recombinant adenovirus vector AdYB-1: implications for oncolytic vector development.
Conditionally replicating adenoviruses are a promising new modality for the treatment of cancer. However, early clinical trials demonstrate that the efficacy of current vectors is limited. Interestingly, DNA replication and production of viral particles do not always correlate with virus-mediated cell lysis and virus release depending on the vector utilized for infection. However, we have previously reported that nuclear accumulation of the human transcription factor YB-1 by regulating the adenoviral E2 late promoter facilitates viral DNA replication of E1-deleted adenovirus vectors which are widely used for cancer gene therapy. Here we report the promotion of virus-mediated cell killing as a new function of the human transcription factor YB-1. In contrast to the E1A-deleted vector dl312 the first-generation adenovirus vector AdYB-1, which overexpresses YB-1 under cytomegalovirus promoter control, led to necrosis-like cell death, virus production, and viral release after infection of A549 and U2OS tumor cell lines. Our data suggest that the integration of YB-1 in oncolytic adenoviruses is a promising strategy for developing oncolytic vectors with enhanced potency against different malignancies.
Institut fuer Experimentelle Onkologie und Therapieforschung, Technische Universitaet Muenchen, Klinikum rechts der Isar, Ismaninger Str. 22, 81675 Munich, Germany.
Gabriel
G
Glockzin
Klaus
K
Mantwill
Karsten
K
Jurchott
Alexandra
A
Bernshausen
Axel
A
Ladhoff
Hans-Dieter
HD
Royer
Bernd
B
Gansbacher
Per Sonne
PS
Holm
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017501:Adenovirus E1B Proteins / Q000502:physiology; D017503:Adenovirus E3 Proteins / Q000032:analysis; D017209:Apoptosis; D002467:Cell Nucleus / Q000821:virology; D003588:Cytopathogenic Effect, Viral; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009687:Nuclear Proteins; D050130:Oncolytic Virotherapy; D011995:Recombination, Genetic; D014771:Virion / Q000502:physiology; D014779:Virus Replication; D051840:Y-Box-Binding Protein 1
D017501:Adenovirus E1B Proteins; D017503:Adenovirus E3 Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; C099609:adenovirus death protein, Adenovirus