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

Michaelis, Martin, Rothweiler, Florian, Agha, Beesan, Barth, Susanne, Voges, Yvonne, Löschmann, Nadine, von Deimling, Andreas, Breitling, Rainer, Doerr, Hans Wilhelm, Rödel, F., and others. (2012) Human neuroblastoma cells with acquired resistance to the p53 activator RITA retain functional p53 and sensitivity to other p53 activating agents. Cell Death & Disease, 3 (-). e294. ISSN 2041-4889. (doi:10.1038/cddis.2012.35) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication)
Official URL
http://dx.doi.org/10.1038/cddis.2012.35

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??M) 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.

Item Type: Article
DOI/Identification number: 10.1038/cddis.2012.35
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 05 Jun 2013 16:27 UTC
Last Modified: 29 May 2019 10:13 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/34050 (The current URI for this page, for reference purposes)
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