Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-κB-dependent mechanism of p53 suppression in tumors
Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-κB-dependent mechanism of p53 suppression in tumors
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DOI：
10.1073/pnas.0508888102
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发表时间：
2005-11-29
影响因子：
11.1
通讯作者：
Gudkov, AV
中科院分区：
文献类型：
--
作者：
Gurova, KV;Hill, JE;Gudkov, AV
肾细胞癌(RCC)通常保留野生型但功能不活跃的P53，它被未知的显性机制抑制。为了帮助揭示这一机制，我们筛选了一个不同的化学文库，以寻找能够恢复P53依赖的反式激活的小分子，该小分子携带有P53反应的报告。在分离到的化合物中有9-氨基吖啶(9AA)的衍生物，包括抗疟疾药物奎纳克林，它能在肾癌和其他类型的癌细胞中强烈地诱导P53功能。这些化合物对P53的诱导不涉及遗传毒性应激，而是通过抑制核因子-kappaB的活性来介导的。与靶向I kappa B kinase2、9AA和Quinacine的药物相比，9AA和Quinacine可以有效地抑制NF-kappa B的基础活性和诱导活性，代表一种以前未描述的类型的抑制剂，将NF-kappa B从反式激活因子转化为反式阻遏因子，导致p65/REIA亚基中非磷酸化Ser-536的非活性核复合体积聚。异位表达I kappa B超抑制物可恢复肾细胞癌中P53的功能，与9AA衍生化合物一样有效。这些发现表明，在许多肿瘤中观察到的P53的完全或部分抑制可能是核因子-kappaB结构性激活的结果。这些结果原则上证明了通过同时抑制核因子-kappaB和单个小分子激活P53来选择性地杀死癌细胞的可能性，并提示了著名的抗疟疾药物奎纳克林的抗癌应用。
Renal cell carcinomas (RCC) commonly retain wild-type but functionally inactive p53, which is repressed by an unknown dominant mechanism. To help reveal this mechanism, we screened a diverse chemical library for small molecules capable of restoring p53-dependent transactivation in RCC cells carrying a p53-responsive reporter. Among the compounds isolated were derivatives of 9-aminoacridine (9AA), including the antimalaria drug quinacrine, which strongly induced p53 function in RCC and other types of cancer cells. Induction of p53 by these compounds does not involve genotoxic stress and is mediated by suppression of NF-kappa B activity. In contrast to agents that target I kappa B kinase 2, 9AA and quinacrine can effectively suppress both basal and inducible activities of NF-kappa B, representing inhibitors of a previously unclescribed type that convert NF-kappa B from a transactivator into a transrepressor, leading to accumulation of inactive nuclear complexes with unphosphorylated Ser-536 in the p65/ReIA subunit. p53 function in RCC can be restored by ectopic expression of a superrepressor of I kappa B as effectively as by 9AA-derived compounds. These findings suggest that the complete or partial repression of p53 observed in many tumors can be the result of constitutive activation of NF-kappa B. The results demonstrate, in principle, the possibility to kill cancer cells selectively through simultaneous inhibition of NF-kappa B and activation of p53 by a single small molecule and suggest anticancer applications for the well known antimalaria drug quinacrine.