NDLI: Human neuroblastoma cells with acquired resistance to the p53 activator RITA retain functional p53 and sensitivity to other p53 activating agents.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Michaelis, M. Rothweiler, F. Agha, B. Barth, S. Voges, Y. Löschmann, N. Von Deimling, A. Breitling, R. Doerr, H. Wilhelm Rödel, F. Speidel, D. Cinatl, J.
Description	Country affiliation: Germany Author Affiliation: Michaelis M ( Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.)
Abstract	Adaptation of wild-type p53 expressing UKF-NB-3 cancer cells to the murine double minute 2 inhibitor nutlin-3 causes de novo p53 mutations at high frequency (13/20) and multi-drug resistance. Here, we show that the same cells respond very differently when adapted to RITA, a drug that, like nutlin-3, also disrupts the p53/Mdm2 interaction. All of the 11 UKF-NB-3 sub-lines adapted to RITA that we established retained functional wild-type p53 although RITA induced a substantial p53 response. Moreover, all RITA-adapted cell lines remained sensitive to nutlin-3, whereas only five out of 10 nutlin-3-adapted cell lines retained their sensitivity to RITA. In addition, repeated adaptation of the RITA-adapted sub-line UKF-NB-3(r)RITA(10 µM) to nutlin-3 resulted in p53 mutations. The RITA-adapted UKF-NB-3 sub-lines displayed no or less pronounced resistance to vincristine, cisplatin, and irradiation than nutlin-3-adapted UKF-NB-3 sub-lines. Furthermore, adaptation to RITA was associated with fewer changes at the expression level of antiapoptotic factors than observed with adaptation to nutlin-3. Transcriptomic analyses indicated the RITA-adapted sub-lines to be more similar at the gene expression level to the parental UKF-NB-3 cells than nutlin-3-adapted UKF-NB-3 sub-lines, which correlates with the observed chemotherapy and irradiation sensitivity phenotypes. In conclusion, RITA-adapted cells retain functional p53, remain sensitive to nutlin-3, and display a less pronounced resistance phenotype than nutlin-3-adapted cells.
File Format	HTM / HTML
e-ISSN	20414889
DOI	10.1038/cddis.2012.35
Journal	Cell Death and Disease
Volume Number	3
Language	English
Publisher	Nature Publishing Group
Publisher Date	2012-04-05
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Research Support, Non-u.s. Gov't Transcriptome Drug Resistance, Neoplasm Neuroblastoma Tumor Suppressor Protein P53 Genetics Proto-oncogene Proteins C-mdm2 Piperazines Drug Therapy Pharmacology Metabolism Drug Effects Vincristine Cisplatin Therapeutic Use Discipline Cell Biology Phenotype Imidazoles Cell Line, Tumor Furans Mutation Apoptosis Cluster Analysis
Content Type	Text
Resource Type	Article

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