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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kappa B-dependent mechanism of p53 suppression in tumors
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Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kappa B-dependent mechanism of p53 suppression in tumors

机译：在肾细胞癌中重新激活p53的小分子揭示了肿瘤中p53抑制的NF-κB依赖性机制

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摘要

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.
机译：肾细胞癌（RCC）通常保留野生型但功能失活的p53，但未知的显性机制可抑制该功能。为了帮助揭示这一机制，我们筛选了多种化学文库，用于检测能够还原携带p53反应性报告基因的RCC细胞中p53依赖性反式激活的小分子。在分离出的化合物中，有9-氨基ac啶（9AA）的衍生物，包括抗疟疾药物奎纳克林（quinacrine），该衍生物强烈诱导p53在RCC和其他类型癌细胞中的功能。这些化合物对p53的诱导不涉及遗传毒性应激，并且是通过抑制NF-κB活性来介导的。与靶向IκB激酶2的药物相反，9AA和奎纳克林可以有效抑制NF-κB的基础活性和诱导活性，这代表了以前未被认可的抑制剂，可将NF-κB从反式激活因子转化为反式抑制因子，从而导致在p65 / ReIA亚基中具有未磷酸化Ser-536的无活性核复合物的积累。异位表达IκB可以像9AA衍生化合物一样有效地恢复RCC中的p53功能。这些发现表明，在许多肿瘤中观察到的p53的完全或部分阻抑可能是NF-κB组成性激活的结果。从原理上讲，这些结果证明了通过同时抑制NF-κB选择性杀死癌细胞的可能性。单个小分子对p53的激活和激活，并为著名的抗疟药奎纳克林提出了抗癌应用。

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