TY  - JOUR
A1  - Michaelis, Martin
A1  - Rothweiler, Florian
A1  - Agha, B.
A1  - Barth, Susanne
A1  - Voges, Yvonne
A1  - Löschmann, Nadine
A1  - Deimling, Andreas von
A1  - Breitling, Rainer
A1  - Doerr, Hans Wilhelm
A1  - Rödel, Franz
A1  - Speidel, Daniel
A1  - Cinatl, Jindrich
T1  - Human neuroblastoma cells with acquired resistance to the p53 activator RITA retain functional p53 and sensitivity to other p53 activating agents
T2  - Cell death and disease
N2  - 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.
KW  - RITA
KW  - nutlin-3
KW  - p53
KW  - p53 activator
KW  - drug resistance
KW  - radiation
Y1  - 2012
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/25330
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-253305
SN  - 2041-4889
VL  - 3
IS  - e294
PB  - Nature Publishing Group
CY  - London [u.a.]
ER  -