Induction of p53-dependent senescence by the MDM2 antagonist nutlin-3a in mouse cells of fibroblast origin

被引:111
作者
Efeyan, Alejo
Ortega-Molina, Ana
Velasco-Miguel, Susana
Herranz, Daniel
Vassilev, Lyubomir T.
Serrano, Manuel
机构
[1] Spanish Natl Canc Res Ctr, Mol Oncol Program, Madrid, Spain
[2] Hoffmann La Roche Inc, Discovery Oncol, Nutley, NJ USA
关键词
D O I
10.1158/0008-5472.CAN-07-0200
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Cellular senescence is emerging as an important in vivo anticancer response elicited by multiple stresses, including currently used chemotherapeutic drugs. Nutlin-3a is a recently discovered small-molecule antagonist of the p53-destabilizing protein murine double minute-2 (MDM2) that induces cell cycle arrest and apoptosis in cancer cells with functional p53. Here, we report that nutlin-3a induces cellular senescence in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. No evidence of drug-induced apoptosis was observed in any case. Nutlin-induced senescence was strictly dependent on the presence of functional p53 as revealed by the fact that cells lacking p53 were completely insensitive to the drug, whereas cells lacking the tumor suppressor alternative reading frame product of the CDKN2A locus underwent irreversible cell cycle arrest. Interestingly, irreversibility was achieved in neoplastic cells faster than in their corresponding parental primary cells, suggesting that nutlin-3a and oncogenic signaling cooperate in activating p53. Our current results suggest that senescence could he a major cellular outcome of cancer therapy by antagonists of the p53-MDM2 interaction, such as nutlin-3a.
引用
收藏
页码:7350 / 7357
页数:8
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