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Senescence induction in renal carcinoma cells by Nutlin-3: a potential therapeutic strategy based on MDM2 antagonism

Authors
Journal
Cancer Letters
0304-3835
Publisher
Elsevier
Publication Date
Volume
353
Issue
2
Identifiers
DOI: 10.1016/j.canlet.2014.07.024
Keywords
  • Renal Cell Carcinoma
  • P53
  • Mdm2
  • Nutlin-3
  • Senescence
  • Targeted Therapy
Disciplines
  • Biology
  • Medicine

Abstract

Abstract Although the role of p53 as a tumour suppressor in renal cell carcinoma (RCC) is unclear, our recent analysis suggests that increased wild-type p53 protein expression is associated with poor outcome. A growing body of evidence also suggests that p53 expression and increased co-expression of MDM2 are linked with poor prognosis in RCC. We have therefore examined whether an MDM2 antagonist; Nutlin-3, might rescue/increase p53 expression and induce growth inhibition or apoptosis in RCC cells that retain wild-type p53. We show that inhibition of p53 suppression by MDM2 in RCC cells promotes growth arrest and p53-dependent senescence – phenotypes known to mediate p53 tumour suppression in vivo. We propose that future investigations of therapeutic strategies for RCC should incorporate MDM2 antagonism as part of strategies aimed at rescuing/augmenting p53 tumour suppressor function.

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