title: Senescence induction in renal carcinoma cells by Nutlin-3: a potential therapeutic strategy based on MDM2 antagonism.
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.
authors: p53/MDM2 Research Group, Department of Molecular and Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, Liverpool L3 9TA, UK.
authors: Radosław
authors: R
authors: Polański
authors: p53/MDM2 Research Group, Department of Molecular and Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, Liverpool L3 9TA, UK.
authors: Aidan P
authors: AP
authors: Noon
authors: Southampton Cancer Research UK Centre, University of Southampton School of Medicine, Southampton, Hampshire, UK.
authors: Jeremy
authors: J
authors: Blaydes
authors: Southampton Cancer Research UK Centre, University of Southampton School of Medicine, Southampton, Hampshire, UK.
authors: Anna
authors: A
authors: Phillips
authors: p53/MDM2 Research Group, Department of Molecular and Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, Liverpool L3 9TA, UK.
authors: Carlos P
authors: CP
authors: Rubbi
authors: Department of Urology, Royal Liverpool University Hospital, Liverpool L7 8XP, UK.
authors: Keith
authors: K
authors: Parsons
authors: p53/MDM2 Research Group, Department of Molecular and Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, Liverpool L3 9TA, UK.
authors: Nikolina
authors: N
authors: Vlatković
authors: p53/MDM2 Research Group, Department of Molecular and Clinical Cancer Medicine, Cancer Research Centre, University of Liverpool, Liverpool L3 9TA, UK. Electronic address: mboyd@liv.ac.uk.
authors: Mark T
authors: MT
authors: Boyd
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007680:Kidney Neoplasms; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D010879:Piperazines; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; Nutlin-3; Renal cell carcinoma; Senescence; Targeted therapy; p53