人前列腺癌细胞中MDM2拮抗剂Nutlin-3的分析
Analysis of the MDM2 antagonist nutlin-3 in human prostate cancer cells.
作者信息
Logan Ian R, McNeill Hesta V, Cook Susan, Lu Xiaohong, Lunec John, Robson Craig N
机构信息
Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle Upon Tyne, UK.
出版信息
Prostate. 2007 Jun 1;67(8):900-6. doi: 10.1002/pros.20568.
BACKGROUND
Small molecule MDM2 antagonists including nutlin-3 have been shown to be effective against a range of cancer cell types and nutlin-3 can inhibit growth of LNCaP xenografts. We compared the efficacy of nutlin-3 in three prostate cancer cell types and provide an insight into the mechanism of nutlin-3.
METHODS
Nutlin-3 efficacy was measured using proliferation assays, cell cycle analysis, apoptosis assays, quantitative RT-PCR, and immunoblotting. Chromatin immunoprecipitation (ChIP) assays were also performed.
RESULTS
Nutlin-3 can specifically inhibit proliferation of LNCaP cells through cell cycle arrest and apoptosis. This coincides with increased levels of the p53-responsive transcripts p21, PUMA, gadd45, and Mdm2 and recruitment of p53 to chromatin. Nutlin-3 also reduces androgen receptor levels, resulting in altered receptor recruitment to chromatin.
CONCLUSION
Our study demonstrates that small molecule MDM2 antagonists might be useful in the treatment of human prostate cancers that retain functional p53 and androgen receptor signaling.
背景
包括Nutlin-3在内的小分子MDM2拮抗剂已被证明对多种癌细胞类型有效，且Nutlin-3可抑制LNCaP异种移植瘤的生长。我们比较了Nutlin-3在三种前列腺癌细胞类型中的疗效，并深入了解了Nutlin-3的作用机制。
方法
使用增殖试验、细胞周期分析、凋亡试验、定量逆转录聚合酶链反应和免疫印迹法测量Nutlin-3的疗效。还进行了染色质免疫沉淀（ChIP）试验。
结果
Nutlin-3可通过细胞周期阻滞和凋亡特异性抑制LNCaP细胞的增殖。这与p53反应性转录本p21、PUMA、gadd45和Mdm2水平的增加以及p53募集到染色质上相吻合。Nutlin-3还降低雄激素受体水平，导致受体募集到染色质的情况发生改变。
结论
我们的研究表明，小分子MDM2拮抗剂可能对保留功能性p53和雄激素受体信号传导的人类前列腺癌治疗有用。
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