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

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37 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Páginas (desde-hasta)1012-1022
Número de páginas11
PublicaciónBritish Journal of Cancer
Volumen105
N.º7
DOI
EstadoPublished - sep. 27 2011

Nota bibliográfica

Funding Information:
This work was supported by operating grants from the Canadian Institutes for Health Research (CIHR) and the Canadian Cancer Society Research Institute through the Terry Fox Foundation (CCSRI and TFRI) to PWKL, doctoral scholarships from the Cancer Research Training Program (CRTP) (DP) and postdoctoral fellowships from the Alberta Heritage Foundation for Medical Research (PM), CRTP (PM, MS, RH), CIHR (MS) and the National Cancer Institute of Canada (MS).

ASJC Scopus Subject Areas

  • Oncology
  • Cancer Research

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