Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-κB-dependent mechanism of p53 suppression in tumors

被引:236
作者
Gurova, KV [1 ]
Hill, JE
Guo, CH
Prokvolit, A
Burdelya, LG
Samoylova, E
Khodyakova, AV
Ganapathi, R
Ganapathi, M
Tararova, ND
Bosykh, D
Lvovskiy, D
Webb, TR
Stark, GR
Gudkov, AV
机构
[1] Cleveland Clin Fdn, Dept Mol Genet, Cleveland, OH 44195 USA
[2] Cleveland Clin Fdn, Taussig Canc Ctr, Cleveland, OH 44195 USA
[3] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA
[4] Chembridge Corp, San Diego, CA 92127 USA
[5] Cleveland BioLabs Inc, Cleveland, OH 44106 USA
关键词
anticancer treatment; apoptosis; chemical library; quinacrine;
D O I
10.1073/pnas.0508888102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
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.
引用
收藏
页码:17448 / 17453
页数:6
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