Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells
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Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells. / Michaelis, M; Rothweiler, F; Barth, S; Cinatl, J; van Rikxoort, M; Löschmann, N; Voges, Y; Breitling, R; von Deimling, A; Rödel, F; Riecken, Kristoffer; Fehse, B; Mack, E; Stiewe, T; Doerr, H W; Speidel, D; Cinatl, J; Riecken, Kristoffer.
In: CELL DEATH DIS, Vol. 2, 01.01.2011, p. e243.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Adaptation of cancer cells from different entities to the MDM2 inhibitor nutlin-3 results in the emergence of p53-mutated multi-drug-resistant cancer cells
AU - Michaelis, M
AU - Rothweiler, F
AU - Barth, S
AU - Cinatl, J
AU - van Rikxoort, M
AU - Löschmann, N
AU - Voges, Y
AU - Breitling, R
AU - von Deimling, A
AU - Rödel, F
AU - Riecken, Kristoffer
AU - Fehse, B
AU - Mack, E
AU - Stiewe, T
AU - Doerr, H W
AU - Speidel, D
AU - Cinatl, J
AU - Riecken, Kristoffer
PY - 2011/1/1
Y1 - 2011/1/1
N2 - Six p53 wild-type cancer cell lines from infrequently p53-mutated entities (neuroblastoma, rhabdomyosarcoma, and melanoma) were continuously exposed to increasing concentrations of the murine double minute 2 inhibitor nutlin-3, resulting in the emergence of nutlin-3-resistant, p53-mutated sublines displaying a multi-drug resistance phenotype. Only 2 out of 28 sublines adapted to various cytotoxic drugs harboured p53 mutations. Nutlin-3-adapted UKF-NB-3 cells (UKF-NB-3(r)Nutlin(10 μM), harbouring a G245C mutation) were also radiation resistant. Analysis of UKF-NB-3 and UKF-NB-3(r)Nutlin(10 μM) cells by RNA interference experiments and lentiviral transduction of wild-type p53 into p53-mutated UKF-NB-3(r)Nutlin(10 μM) cells revealed that the loss of p53 function contributes to the multi-drug resistance of UKF-NB-3(r)Nutlin(10 μM) cells. Bioinformatics PANTHER pathway analysis based on microarray measurements of mRNA abundance indicated a substantial overlap in the signalling pathways differentially regulated between UKF-NB-3(r)Nutlin(10 μM) and UKF-NB-3 and between UKF-NB-3 and its cisplatin-, doxorubicin-, or vincristine-resistant sublines. Repeated nutlin-3 adaptation of neuroblastoma cells resulted in sublines harbouring various p53 mutations with high frequency. A p53 wild-type single cell-derived UKF-NB-3 clone was adapted to nutlin-3 in independent experiments. Eight out of ten resulting sublines were p53-mutated harbouring six different p53 mutations. This indicates that nutlin-3 induces de novo p53 mutations not initially present in the original cell population. Therefore, nutlin-3-treated cancer patients should be carefully monitored for the emergence of p53-mutated, multi-drug-resistant cells.
AB - Six p53 wild-type cancer cell lines from infrequently p53-mutated entities (neuroblastoma, rhabdomyosarcoma, and melanoma) were continuously exposed to increasing concentrations of the murine double minute 2 inhibitor nutlin-3, resulting in the emergence of nutlin-3-resistant, p53-mutated sublines displaying a multi-drug resistance phenotype. Only 2 out of 28 sublines adapted to various cytotoxic drugs harboured p53 mutations. Nutlin-3-adapted UKF-NB-3 cells (UKF-NB-3(r)Nutlin(10 μM), harbouring a G245C mutation) were also radiation resistant. Analysis of UKF-NB-3 and UKF-NB-3(r)Nutlin(10 μM) cells by RNA interference experiments and lentiviral transduction of wild-type p53 into p53-mutated UKF-NB-3(r)Nutlin(10 μM) cells revealed that the loss of p53 function contributes to the multi-drug resistance of UKF-NB-3(r)Nutlin(10 μM) cells. Bioinformatics PANTHER pathway analysis based on microarray measurements of mRNA abundance indicated a substantial overlap in the signalling pathways differentially regulated between UKF-NB-3(r)Nutlin(10 μM) and UKF-NB-3 and between UKF-NB-3 and its cisplatin-, doxorubicin-, or vincristine-resistant sublines. Repeated nutlin-3 adaptation of neuroblastoma cells resulted in sublines harbouring various p53 mutations with high frequency. A p53 wild-type single cell-derived UKF-NB-3 clone was adapted to nutlin-3 in independent experiments. Eight out of ten resulting sublines were p53-mutated harbouring six different p53 mutations. This indicates that nutlin-3 induces de novo p53 mutations not initially present in the original cell population. Therefore, nutlin-3-treated cancer patients should be carefully monitored for the emergence of p53-mutated, multi-drug-resistant cells.
KW - Humans
KW - Mutation
KW - Tumor Cells, Cultured
KW - Tumor Suppressor Protein p53/metabolism
KW - Imidazoles/pharmacology
KW - RNA Interference
KW - Caspase 3/metabolism
KW - Antineoplastic Agents/pharmacology
KW - Adaptation, Biological/drug effects
KW - Caspase 7/metabolism
KW - Drug Resistance, Neoplasm/genetics
KW - Piperazines/pharmacology
KW - Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors/metabolism
KW - Humans
KW - Mutation
KW - Tumor Cells, Cultured
KW - Tumor Suppressor Protein p53/metabolism
KW - Imidazoles/pharmacology
KW - RNA Interference
KW - Caspase 3/metabolism
KW - Antineoplastic Agents/pharmacology
KW - Adaptation, Biological/drug effects
KW - Caspase 7/metabolism
KW - Drug Resistance, Neoplasm/genetics
KW - Piperazines/pharmacology
KW - Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors/metabolism
U2 - 10.1038/cddis.2011.129
DO - 10.1038/cddis.2011.129
M3 - SCORING: Journal article
C2 - 22170099
VL - 2
SP - e243
JO - CELL DEATH DIS
JF - CELL DEATH DIS
SN - 2041-4889
ER -
