title: Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kappaB-dependent mechanism of p53 suppression in tumors.
abstract: 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-kappaB activity. In contrast to agents that target IkappaB kinase 2, 9AA and quinacrine can effectively suppress both basal and inducible activities of NF-kappaB, representing inhibitors of a previously undescribed type that convert NF-kappaB from a transactivator into a transrepressor, leading to accumulation of inactive nuclear complexes with unphosphorylated Ser-536 in the p65/RelA subunit. p53 function in RCC can be restored by ectopic expression of a superrepressor of IkappaB 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-kappaB. The results demonstrate, in principle, the possibility to kill cancer cells selectively through simultaneous inhibition of NF-kappaB and activation of p53 by a single small molecule and suggest anticancer applications for the well known antimalaria drug quinacrine.
authors.affiliation: Department of Molecular Genetics, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. gudkov@ccf.org
authors.forename: Katerina V
authors.initials: KV
authors.lastname: Gurova
authors.forename: Jason E
authors.initials: JE
authors.lastname: Hill
authors.forename: Canhui
authors.initials: C
authors.lastname: Guo
authors.forename: Anatoly
authors.initials: A
authors.lastname: Prokvolit
authors.forename: Lyudmila G
authors.initials: LG
authors.lastname: Burdelya
authors.forename: Eugenia
authors.initials: E
authors.lastname: Samoylova
authors.forename: Anna V
authors.initials: AV
authors.lastname: Khodyakova
authors.forename: Ram
authors.initials: R
authors.lastname: Ganapathi
authors.forename: Mahrukh
authors.initials: M
authors.lastname: Ganapathi
authors.forename: Natalia D
authors.initials: ND
authors.lastname: Tararova
authors.forename: Dmitry
authors.initials: D
authors.lastname: Bosykh
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Lvovskiy
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Webb
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
mesh_terms: D000585:Aminacrine / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D003124:Colorimetry; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011796:Quinacrine / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D000585:Aminacrine; D001616:beta-Galactosidase; D011796:Quinacrine