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

• Verfasst von: Michaelis, Martin [VerfasserIn]
• Verfasst von: Deimling, Andreas von [VerfasserIn]
• Titel: Human neuroblastoma cells with acquired resistance to the p53 activator RITA retain functional p53 and sensitivity to other p53 activating agents
• Verf.angabe: M. Michaelis, F. Rothweiler, B. Agha, S. Barth, Y. Voges, N. Löschmann, A. von Deimling, R. Breitling, H. Wilhelm Doerr, F. Rödel, D. Speidel, and J. Cinatl Jr
• Fussnoten: Gesehen am 29.11.2018
• Titel Quelle: Enthalten in: Cell death & disease
• Jahr Quelle: 2012
• Band/Heft Quelle: 3(2012,4) Artikelnummer e294, 8 Seiten
• ISSN Quelle: 2041-4889
• DOI: doi:10.1038/cddis.2012.35
• Sprache: eng
• K10plus-PPN: 1584617020

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-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.