Academic Journal
Downmodulation of El A Protein Expression as a Novel Strategy to Design Cancer-Selective Adenoviruses
| Title: | Downmodulation of El A Protein Expression as a Novel Strategy to Design Cancer-Selective Adenoviruses |
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| Authors: | Hong Jiang, Ramon Alemany, Candelaria Gomez-Manzano, Diana R. Medrano, Michael G. Lemoine, Melissa V. Olson, Marta M. Alonso, Ok-Hee Lee, Charles C. Conrad, W.K. Alfred Yung, Juan Fueyo |
| Source: | Neoplasia: An International Journal for Oncology Research, Vol 7, Iss 8, Pp 723-729 (2005) |
| Publisher Information: | Elsevier, 2005. |
| Publication Year: | 2005 |
| Collection: | LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| Subject Terms: | glioma, oncolytic, adenovirus, E1A, CR1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| More Details: | Oncolytic adenoviruses are being tested as potential therapies for human malignant tumors, including gliomas. Here we report for the first time that a mutation in the E1A gene results in low levels of ElA protein, conditioning the replication of mutant adenoviruses specifically to cancer cells. In this study, we compared the oncolytic potencies of three mutant adenoviruses encompassing deletions within the CRi (Delta-39), CR2 (Delta-24) regions, or both regions (Delta-24/39) of the ElA protein. Delta-39, Delta-24 induced a cytopathic effect with similar efficiency in glioma cells, a comparable capacity for replication. Importantly, the activity of Delta-39 was significantly attenuated compared to Delta-24 in proliferating normal human astrocytes. Direct analyses of the activation of E2F-1 promoter demonstrated the inability of Delta-39 to induce S-phase-related transcriptional activity in normal cells. Interestingly, ElA protein levels in cells infected with Delta-39 were remarkably downmodulated. Furthermore, protein stability studies revealed enhanced degradation of CRi mutant ElA proteins, inhibition of the proteasome activity resulted in the striking rescue of ElA levels. We conclude that the level of ElA protein is a critical determinant of oncolytic phenotype, we propose a completely novel strategy for the design, construction of conditionally replicative adenoviruses. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1476-5586 1522-8002 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S1476558605801046; https://doaj.org/toc/1476-5586; https://doaj.org/toc/1522-8002 |
| DOI: | 10.1593/neo.04793 |
| Access URL: | https://doaj.org/article/491e1777705e404cb344c8429991fbba |
| Accession Number: | edsdoj.491e1777705e404cb344c8429991fbba |
| Database: | Directory of Open Access Journals |
| ISSN: | 14765586 15228002 |
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| DOI: | 10.1593/neo.04793 |
| Published in: | Neoplasia: An International Journal for Oncology Research |
| Language: | English |