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

Oncogene volume 27, pages 3081–3090 (2008)Cite this article

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.

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Acknowledgements

This research was funded by Cancer Research UK (grant C9423/A4119). We acknowledge the excellent technical assistance of Ken Blight in the Electron Microscopy Department, Cancer Research UK London Research Institute.

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Authors and Affiliations

  1. Centre for Molecular Oncology, Cancer Research UK Clinical Centre, Institute of Cancer, Barts and the London Queen Mary's School of Medicine, London, UK

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

  2. FACS Laboratory, Cancer Research UK London Research Institute, London, UK

    A Eddaoudi

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  1. S K Baird
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  2. J L Aerts
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  3. A Eddaoudi
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  4. M Lockley
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  5. N R Lemoine
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Correspondence to I A McNeish.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Baird, S., Aerts, J., Eddaoudi, A. et al. Oncolytic adenoviral mutants induce a novel mode of programmed cell death in ovarian cancer. Oncogene 27, 3081–3090 (2008). https://doi.org/10.1038/sj.onc.1210977

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