Stabilisation of p53 enhances reovirus-induced apoptosis and virus spread through p53-dependent NF-κB activation

D. Pan, L.-Z. Pan, R. Hill, P. Marcato, M. Shmulevitz, L. T. Vassilev, P. W. K. Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Naturally oncolytic reovirus preferentially kills cancer cells, making it a promising cancer therapeutic. Mutations in tumour suppressor p53 are prevalent in cancers, yet the role of p53 in reovirus oncolysis is relatively unexplored.

Methods: Human cancer cell lines were exposed to Nutlin-3a, reovirus or a combination of the two and cells were processed for reovirus titration, western blot, real-time PCR and apoptosis assay using Annexin V and 7-AAD staining. Confocal microscopy was used to determine translocation of the NF-κB p65 subunit.

Results: We show that despite similar reovirus replication in p53+/+ and p53−/− cells, stabilisation of p53 by Nutlin-3a significantly enhanced reovirus-induced apoptosis and hence virus release and dissemination while having no direct effect on virus replication. Enhanced apoptosis by Nutlin-3a was not observed in p53−/− or p53 knockdown cells; however, increased expression of Bax and p21 are required. Moreover, elevated NF-κB activation in reovirus-infected cells following Nutlin-3a treatment was necessary for enhanced reovirus-induced apoptosis, as synergistic cytotoxicity was overcome by specific NF-κB inhibitors.

Conclusion: Nutlin-3a treatment enhances reovirus-induced apoptosis and virus spread through p53-dependent NF-κB activation, and combination of reovirus and Nutlin-3a might represent an improved therapy against cancers harbouring wild-type p53.
Original languageEnglish
Pages (from-to)1012-1022
Number of pages11
JournalBritish Journal of Cancer
Volume105
Issue number7
DOIs
Publication statusPublished - 27 Sep 2011
Externally publishedYes

Keywords

  • reovirus
  • Nutlin-3a
  • NF-kB
  • apoptosis

Fingerprint

Dive into the research topics of 'Stabilisation of p53 enhances reovirus-induced apoptosis and virus spread through p53-dependent NF-κB activation'. Together they form a unique fingerprint.

Cite this