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

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 
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-3rRITA10 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.
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Metadaten
Author:Martin Michaelis, Florian Rothweiler, B Agha, Susanne Barth, Yvonne Voges, Nadine Löschmann, Andreas von Deimling, Rainer Breitling, Hans-Wilhelm Doerr, Franz Rödel, Daniel Speidel, Jindrich Cinatl
URN:urn:nbn:de:hebis:30:3-253305
DOI:http://dx.doi.org/10.1038/cddis.2012.35
ISSN:2041-4889
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=22476102
Parent Title (English):Cell death and disease
Publisher:Nature Publishing Group
Place of publication:London [u.a.]
Document Type:Article
Language:English
Date of Publication (online):2012/04/05
Date of first Publication:2012/04/05
Publishing Institution:Univ.-Bibliothek Frankfurt am Main
Release Date:2012/08/10
Tag:RITA; drug resistance; nutlin-3; p53; p53 activator; radiation
Volume:3
Issue:e294
Pagenumber:8
First Page:1
Last Page:8
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Weitergabe unter gleichen Bedingungen

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