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.
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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DOI：
10.1038/cddis.2011.129
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发表时间：
2011-12-15
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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作者：
来自 p53 罕见突变实体（神经母细胞瘤、横纹肌肉瘤和黑色素瘤）的 6 种 p53 野生型癌细胞系连续暴露于浓度不断增加的鼠双微 2 抑制剂 nutlin-3，导致出现了 nutlin-3 耐药、p53 突变亚系，表现出多药耐药表型。适应各种细胞毒性药物的 28 个亚系中，只有 2 个存在 p53 突变。 Nutlin-3 适应的 UKF-NB-3 细胞（UKF-NB-3rNutlin10μM，带有 G245C 突变）也具有辐射抗性。通过RNA干扰实验和将野生型p53慢病毒转导到p53突变的UKF-NB-3rNutlin10 μM细胞中对UKF-NB-3和UKF-NB-3rNutlin10 μM细胞的分析表明，p53功能的丧失有助于UKF-NB-3rNutlin10 μM细胞的多药耐药性。基于 mRNA 丰度微阵列测量的生物信息学 PANTHER 通路分析表明，UKF-NB-3rNutlin10μM 和 UKF-NB-3 之间以及 UKF-NB-3 及其顺铂、阿霉素或长春新碱耐药亚系之间差异调节的信号通路存在显着重叠。神经母细胞瘤细胞的重复 nutlin-3 适应导致亚系高频率地含有各种 p53 突变。在独立实验中，p53 野生型单细胞衍生的 UKF-NB-3 克隆适应 nutlin-3。所得的十个亚系中有八个是 p53 突变的，包含六种不同的 p53 突变。这表明 nutlin-3 诱导最初不存在于原始细胞群中的从头 p53 突变。因此，应仔细监测接受 nutlin-3 治疗的癌症患者是否出现 p53 突变、多重耐药细胞。
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-3rNutlin10 μM, harbouring a G245C mutation) were also radiation resistant. Analysis of UKF-NB-3 and UKF-NB-3rNutlin10 μM cells by RNA interference experiments and lentiviral transduction of wild-type p53 into p53-mutated UKF-NB-3rNutlin10 μM cells revealed that the loss of p53 function contributes to the multi-drug resistance of UKF-NB-3rNutlin10 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-3rNutlin10 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.
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影响因子：
8
作者：
Aziz, M. H.;Shen, H.;Maki, C. G.
通讯作者：
Maki, C. G.
影响因子：
11.2
作者：
Michaelis, Martin;Rothweiler, Florian;Cinatl, Jindrich, Jr.
通讯作者：
Cinatl, Jindrich, Jr.
影响因子：
8.8
作者：
Rieger, K. M.;Little, A. F.;Swart, J. M.;Kastrinakis, W. V.;Fitzgerald, J. M.;Hess, D. T.;Libertino, J. A.;Summerhayes, I. C.
通讯作者：
Summerhayes, I. C.
DOI：
10.1016/s0921-8777(99)00053-1
发表时间：
1999-12-07
期刊：
MUTATION RESEARCH-DNA REPAIR
影响因子：
--
作者：
Meng, L;Lin, L;Nadji, M
通讯作者：
Nadji, M
影响因子：
3.7
作者：
Levina V;Marrangoni AM;DeMarco R;Gorelik E;Lokshin AE
通讯作者：
Lokshin AE