Michaelis, Martin and Rothweiler, F. and Barth, S. and Cinatl, J. and van Rikxoort, M. and Löschmann, N. and Voges, Y. and Breitling, R. and von Deimling, A. and Rödel, F. and Weber, K. and Fehse, B. and Mack, E. and Stiewe, T. and Doerr, H.W. and Speidel, D. and Cinatl, J. (2011) Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. Cell Death and Disease, 2 (12). e243. ISSN 2041-4889.
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Six p53 wild-type cancer cell lines from infrequently p53-mutated entities (neuroblastoma, rhabdomyosarcoma, and melanoma) were continuously exposed to increasing concentrations of the murine double minute 2 inhibitor nutlin-3, resulting in the emergence of nutlin-3-resistant, p53-mutated sublines displaying a multi-drug resistance phenotype. Only 2 out of 28 sublines adapted to various cytotoxic drugs harboured p53 mutations. Nutlin-3-adapted UKF-NB-3 cells (UKF-NB-3rNutlin10 μM, harbouring a G245C mutation) were also radiation resistant. Analysis of UKF-NB-3 and UKF-NB-3rNutlin10 μM cells by RNA interference experiments and lentiviral transduction of wild-type p53 into p53-mutated UKF-NB-3rNutlin10 μM cells revealed that the loss of p53 function contributes to the multi-drug resistance of UKF-NB-3rNutlin10 μM cells. Bioinformatics PANTHER pathway analysis based on microarray measurements of mRNA abundance indicated a substantial overlap in the signalling pathways differentially regulated between UKF-NB-3rNutlin10 μM and UKF-NB-3 and between UKF-NB-3 and its cisplatin-, doxorubicin-, or vincristine-resistant sublines. Repeated nutlin-3 adaptation of neuroblastoma cells resulted in sublines harbouring various p53 mutations with high frequency. A p53 wild-type single cell-derived UKF-NB-3 clone was adapted to nutlin-3 in independent experiments. Eight out of ten resulting sublines were p53-mutated harbouring six different p53 mutations. This indicates that nutlin-3 induces de novo p53 mutations not initially present in the original cell population. Therefore, nutlin-3-treated cancer patients should be carefully monitored for the emergence of p53-mutated, multi-drug-resistant cells.
|Uncontrolled keywords:||nutlin-3; MDM2; p53; chemoresistance; chemotherapy|
|Divisions:||Faculties > Science Technology and Medical Studies > School of Biosciences|
|Depositing User:||Sue Davies|
|Date Deposited:||08 Oct 2012 15:45|
|Last Modified:||05 Feb 2013 09:32|
|Resource URI:||http://kar.kent.ac.uk/id/eprint/31392 (The current URI for this page, for reference purposes)|
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