E1A-induced apoptosis does not prevent replication of adenoviruses with deletion of E1b in majority of infected cancer cells.
Apoptotic pathways are initiated as a cellular defense mechanism to eliminate adenovirus-infected cells. We have investigated how E1A-induced apoptosis interferes with viral replication in cancer cells. We found that E1B19K alone can efficiently suppress E1A-induced apoptosis in cancer cells. Viruses deleted for both E1B19K and E1B55K resulted in cellular DNA degradation. However, less than 20% of human lung cancer cells infected with a virus deleted for both E1B19K and E1B55 K had evidence of chromatin condensation and multiple-micronuclei formation (apoptotic hallmarks); these cells could not produce infectious viral particles. The majority of cancer cells infected with viruses deleted for the entire E1b gene did not undergo extended apoptosis and produced abundant viral progeny. Thus, only a fraction of cancer cells underwent apoptosis and did not allow E1b-deleted viruses to replicate, while the majority of cancer cells were resistant to E1A-induced apoptosis and could support virus-selective replication. The results of this study imply that, in addition to inhibiting E1A-induced apoptosis, E1B proteins may contribute other important roles in the viral life cycle. Our results also suggest that combining virus-induced apoptosis and selective viral replication into one vector will be a novel approach to destroy cancer cells.
Rao
Xiao-Mei
XM
Brown Cancer Center, University of Louisville Medical School, Kentucky 40202, USA.
Tseng
Michael T
MT
Zheng
Xinyu
X
Dong
Yanbin
Y
Jamshidi-Parsian
Azemat
A
Thompson
Timothy C
TC
Brenner
Malcolm K
MK
McMasters
Kelly M
KM
Zhou
Heshan Sam
HS
D000257:Adenoviridae Infections / Q000473:pathology / Q000821:virology*; D017500:Adenovirus E1A Proteins / Q000502:physiology*; D017501:Adenovirus E1B Proteins / Q000235:genetics*; D000260:Adenoviruses, Human / Q000502:physiology*; D017209:Apoptosis; D015153:Blotting, Western; D002843:Chromatin / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005822:Genetic Vectors; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000821:virology*; D048629:Micronuclei, Chromosome-Defective; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D017500:Adenovirus E1A Proteins; D017501:Adenovirus E1B Proteins; D002843:Chromatin; D004279:DNA, Viral