title: Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient in p53Ser46 phosphorylation.
abstract: The p53 tumor suppressor protein plays key roles in protecting cells from tumorigenesis. Phosphorylation of p53 at Ser46 (p53Ser46) is considered to be a crucial modification regulating p53-mediated apoptosis. Because the activity of p53 is impaired in most human cancers, restoration of wild-type p53 (wt-p53) function by its gene transfer or by p53-reactivating small molecules has been extensively investigated. The p53-reactivating compounds Nutlin-3 and RITA activate p53 in the absence of genotoxic stress by antagonizing the action of its negative regulator Mdm2. Although controversial, Nutlin-3 was shown to induce p53-mediated apoptosis in a manner independent of p53 phosphorylation. Recently, RITA was shown to induce apoptosis by promoting p53Ser46 phosphorylation. Here we examined whether Nutlin-3 or RITA can overcome resistance to p53-mediated apoptosis in p53-resistant tumor cell lines lacking the ability to phosphorylate p53Ser46. We show that Nutlin-3 did not rescue the apoptotic defect of a Ser46 phosphorylation-defective p53 mutant in p53-sensitive tumor cells, and that RITA neither restored p53Ser46 phosphorylation nor induced apoptosis in p53Ser46 phosphorylation-deficient cells retaining wt-p53. Furthermore, treatment with Nutlin-3 or RITA together with adenoviral p53 gene transfer also failed to induce apoptosis in p53Ser46 phosphorylation-deficient cells either expressing or lacking wt-p53. These results indicate that neither Nutlin-3 nor RITA in able to induce p53-mediated apoptosis in the absence of p53Ser46 phosphorylation. Thus, the dysregulation of this phosphorylation in tumor cells may be a critical factor that limits the efficacy of these p53-based cancer therapies.
authors.affiliation: Section of Molecular Embryology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.
authors.forename: Teng
authors.initials: T
authors.lastname: Ma
authors.forename: Shumpei
authors.initials: S
authors.lastname: Yamada
authors.forename: Solachuddin J A
authors.initials: SJ
authors.lastname: Ichwan
authors.forename: Sachiko
authors.initials: S
authors.lastname: Iseki
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ohtani
authors.forename: Megumi
authors.initials: M
authors.lastname: Otsu
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Ikeda
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053148:Caspase 3; D045744:Cell Line, Tumor; D005663:Furans / Q000494:pharmacology*; D016158:Genes, p53; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D005663:Furans; D007093:Imidazoles; C118989:NSC 652287; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; D012694:Serine; C482205:nutlin 3; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3