Vaccinia virus induces programmed necrosis in ovarian cancer cells

Whilding, L., Archibald, K., Kulbe, H., Balkwill, F., Oberg, D. and Mcneish, I. (2013) Vaccinia virus induces programmed necrosis in ovarian cancer cells. Molecular Therapy, 21(11), pp. 2074-2086. (doi: 10.1038/mt.2013.195)

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The mechanisms by which oncolytic vaccinia virus induces tumour cell death are poorly understood. We have evaluated cell death pathways following infection of ovarian cancer cells with both wild-type and thymidine kinase-deleted (dTK) Lister strain vaccinia. We show that death does not rely upon classical apoptosis despite the appearances of some limited apoptotic features, including phosphatidylserine externalisation and appearance of sub-G1 DNA populations. Vaccinia infection induces marked lipidation of LC3 proteins, but there is no general activation of the autophagic process and cell death does not rely upon autophagy induction. We show that vaccinia induces necrotic morphology on transmission electron microscopy, accompanied by marked by reductions in intracellular ATP, altered mitochondrial metabolism and release of high mobility group box 1 (HMGB1) protein. This necrotic cell death appears regulated, as infection induces formation of a RIP1/caspase-8 complex. In addition, pharmacological inhibition of both RIP1 and substrates downstream of RIP1, including MLKL, significantly attenuate cell death. Blockade of TNF-α, however, does not alter virus efficacy, suggesting that necrosis does not result from autocrine cytokine release. Overall, these results show that, in ovarian cancer cells, vaccinia virus causes necrotic cell death that is mediated through a programmed series of events.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Mcneish, Professor Iain
Authors: Whilding, L., Archibald, K., Kulbe, H., Balkwill, F., Oberg, D., and Mcneish, I.
Subjects:R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Molecular Therapy
ISSN (Online):1525-0024

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