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

• A sub-set of patients with RCC that retain wild-type p53 exhibits a poor prognosis.
• Wild-type p53 constitutes a potential therapeutic target in these RCC patients.
• Nutlin-3 is a prototype competitive inhibitor of p53-MDM2 interaction.
• Inhibiting p53-MDM2 interaction in p53 wild-type RCC cells induces senescence.
• Senescence induction is a potent tumour suppressive process.
• Antagonising p53 inhibition by MDM2 provides a novel therapeutic opportunity in RCC.

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.