Depletion of mutant p53 and cytotoxicity of histone deacetylase inhibitors
Depletion of mutant p53 and cytotoxicity of histone deacetylase inhibitors
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DOI：
10.1158/0008-5472.can-04-3433
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发表时间：
2005-08-15
期刊：
影响因子：
11.2
通讯作者：
Fojo, T
中科院分区：
文献类型：
--
作者：
Blagosklonny, MV;Trostel, S;Fojo, T
突变型P53是药物干预的肿瘤特异性靶点。我们发现，组蛋白脱乙酰酶抑制剂，如FR901228和曲古抑素A，在癌细胞系中完全耗尽突变型p53。在这种耗尽之前，诱导了P53调节的转录。在用过去的脱乙酰酶抑制剂处理过突变型p53的细胞中，DNA损伤进一步增强了p53的反式功能。此外，组蛋白脱乙酰酶抑制剂对具有突变型p53的细胞具有优先的细胞毒性，而不是对缺乏野生型p53的细胞。我们认为，通过恢复或模仿P53的反式功能，历史上的脱乙酰酶抑制剂启动了突变型P53的降解。由于突变型P53高度表达，突变型P53样功能的突然恢复对具有突变型P53的细胞具有高度的细胞毒作用。从更广泛的角度来看，这表明在存在癌症特异性改变(如突变的p53)的情况下，如何通过靶向非癌症特异性靶点(如组蛋白脱乙酰酶)来实现选择性。
Mutant p53 is a cancer-specific target for pharmacologic intervention. We show that histone deacetylase inhibitors such as FR901228 and trichostatin A completely depleted mutant p53 in cancer cell lines. This depletion was preceded by induction of p53-regulated transcription. In cells with mutant p53 pretreated with historic deacetylase inhibitors, DNA damage further enhanced the p53 trans-function. Furthermore, histone deacetylase inhibitors were preferentially cytotoxic to cells with mutant p53 rather than to cells lacking wild-type p53. We suggest that, by either restoring or mimicking p53 trans-functions, historic deacetylase inhibitors initiate degradation of mutant p53. Because mutant p53 is highly expressed, a sudden restoration of p53-like functions is highly cytotoxic to cells with mutant p53. In a broader perspective, this shows how selectivity may be achieved by targeting a non-cancer-specific target, such as histone deacetylases, in the presence of a cancer-specific alteration, such as mutant p53.