Oncolytic adenoviral mutants induce a novel mode of programmed cell death in ovarian cancer
| Autor: | Nicholas R. Lemoine, Joeri L. Aerts, Sarah K. Baird, Iain A. McNeish, Michelle Lockley, A Eddaoudi |
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| Přispěvatelé: | Laboratory of Molecullar and Cellular Therapy, Physiology |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Programmed cell death Cell Survival Virus Replication/physiology Apoptosis Cell Survival/genetics Biology Cell Death/genetics Virus Replication medicine.disease_cause Transfection Article Adenoviridae Necrosis Necrosis/genetics Ovarian Neoplasms/genetics Apoptosis/genetics Autophagy Genetics medicine Tumor Cells Cultured Humans Mitochondria/physiology Adenoviridae/genetics Molecular Biology Ovarian Neoplasms Cell Death Cancer Adenovirus Death Protein medicine.disease Virology Mitochondria Oncolytic virus Oncolytic Viruses Adenovirus E1A Proteins/genetics Lysosomes/physiology Cancer research Mutant Proteins Female Oncolytic Viruses/genetics Adenovirus E1A Proteins Autophagy/physiology Mutant Proteins/genetics Lysosomes Carcinogenesis |
| Popis: | Oncolytic adenoviral mutants have considerable activity in ovarian cancer. However, the mechanisms by which they induce cell death remain uncertain. dl922-947, which contains a 24 bp deletion in E1A CR2, is more potent than both E1A wild-type adenoviruses and the E1B-55K deletion mutant dl1520 (Onyx-015). We investigated the mode of death induced by three E1A CR2-deleted replicating adenoviruses in models of ovarian cancer and also the importance of E3 11.6 (adenovirus death protein) in determining this mode of death. Ovarian cancer cells were infected with dl922-947 (E3 11.6+) and dlCR2 (E3 11.6-). We also generated dlCR2 tSmac, which also encodes the gene for processed Smac/DIABLO. Classical apoptosis does not occur in adenoviral cell death and there is no role for mitochondria. Expression of Smac/DIABLO does not enhance cytotoxicity nor increase apoptotic features. A role for cathepsins and lysosomal membrane permeability was excluded. Autophagy is induced, but is not the mode of death and may act as a cell survival mechanism. There is no evidence of pure necrosis, while the presence of E3 11.6 does not modulate the mode or extent of cell death. Thus, E1A CR2-deleted oncolytic adenoviral cytotoxicity in ovarian cancer may define a novel mode of programmed cell death. |
| Databáze: | OpenAIRE |
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