Selective replication of E1B55K-deleted adenoviruses depends on enhanced E1A expression in cancer cells.
E1B55K-deleted dl1520 could selectively replicate in cancer cells and has been used in clinical trials as an antitumor agent. The mechanism of virus selective replication in cancer cells, including a possible role of p53, is unclear. Studies with established cancer cell lines have demonstrated that some cancer cells are resistant to dl1520 replication, regardless of the p53 status. Hep3B cells supported the E1b-deleted adenoviruses to replicate, whereas Saos2 cells were resistant to viral replication. We applied p53-null Hep3B and Saos2 cells as models to clarify the replication ability of E1B55K-deleted adenoviruses with different expression levels of E1a. We show that lower E1A expression in Saos2 may be the reason for the poor replication in some cancer cells due to the fact that E1a promoter was less activated in Saos2 than in Hep3B. We also demonstrate that the E1B55K protein can increase E1A expression in Saos2 cells for efficient virus replication. In addition, the upstream regions of the E1a promoter have transcriptional activity in Hep3B cells but not in Saos2 cells. The viral E1B55K protein may activate cancer cellular factor(s) that targets the upstream regions of the E1a gene to increase its expression. This is the first study demonstrating that E1B55K protein affects the E1A production levels that is related to cancer selective replication. Our studies have suggested that increase of E1A expression from E1b-deleted adenoviruses may enhance killing cancer cells that otherwise are resistant to viral replication.
Zheng
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James Graham Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Rao
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Snodgrass
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McMasters
K M
KM
Zhou
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HS
D000256:Adenoviridae / Q000235:genetics* / Q000502:physiology; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism*; D017502:Adenovirus E2 Proteins / Q000235:genetics; D002453:Cell Cycle; D045744:Cell Line, Tumor; D017353:Gene Deletion; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D009369:Neoplasms / Q000145:classification / Q000473:pathology / Q000628:therapy*; D011401:Promoter Regions, Genetic; D015854:Up-Regulation; D014779:Virus Replication
D017500:Adenovirus E1A Proteins; D017502:Adenovirus E2 Proteins