Oncolytic adenoviral mutants induce a novel mode of programmed cell death in ovarian cancer

S K Baird, J L Aerts, A Eddaoudi, M Lockley, N R Lemoine, I A McNeish

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3081-3090
Number of pages10
JournalONCOGENE
Volume27
Issue number22
DOIs
Publication statusPublished - 2008

Keywords

  • Adenoviridae/genetics
  • Adenovirus E1A Proteins/genetics
  • Apoptosis/genetics
  • Autophagy/physiology
  • Cell Death/genetics
  • Cell Survival/genetics
  • Female
  • Humans
  • Lysosomes/physiology
  • Mitochondria/physiology
  • Mutant Proteins/genetics
  • Necrosis/genetics
  • Oncolytic Viruses/genetics
  • Ovarian Neoplasms/genetics
  • Transfection
  • Tumor Cells, Cultured
  • Virus Replication/physiology

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