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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

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 d...

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Hauptverfasser: Michaelis, Martin (VerfasserIn) , Rothweiler, F. (VerfasserIn) , Barth, S. (VerfasserIn) , Cinatl, J. (VerfasserIn) , Rikxoort, M. van (VerfasserIn) , Löschmann, N. (VerfasserIn) , Voges, Y. (VerfasserIn) , Breitling, R. (VerfasserIn) , Deimling, Andreas von (VerfasserIn) , Rödel, F. (VerfasserIn) , Weber, Kristoffer (VerfasserIn) , Fehse, Boris (VerfasserIn) , Mack, E. (VerfasserIn) , Stiewe, T. (VerfasserIn) , Doerr, Hans Wilhelm (VerfasserIn) , Speidel, D. (VerfasserIn) , Cinatl, J. Jr. (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 15 December 2011
In: Cell death & disease
Year: 2011, Jahrgang: 2, Pages: 1-8
ISSN:2041-4889
Online-Zugang:Verlag, Volltext: http://www.nature.com/cddis/journal/v2/n12/full/cddis2011129a.html
Volltext
Verfasserangaben:M. Michaelis, F. Rothweiler, S. Barth, J. Cinatl, M. van Rikxoort, N. Löschmann, Y. Voges, R. Breitling, A. von Deimling, F. Rödel, K. Weber, B. Fehse, E. Mack, T. Stiewe, H.W. Doerr, D. Speidel and J. Cinatl
Beschreibung
Zusammenfassung: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.
Beschreibung:Online Resource
ISSN:2041-4889

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