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Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient for p53Ser46 phosphorylation

Teng, Ma and Yamada, Shumpei and Ichwan, Solachuddin J. A. and Ohtani, Kiyoshi and Otsu, Megumi and Ikeda, Masa-Aki (2012) Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient for p53Ser46 phosphorylation. Biochemical and Biophysical Research Communications, 417 (3). pp. 931-937. ISSN 0006-291X

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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 without 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 and 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 of 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 Nutlin-3 and RITA are unable 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.

Item Type: Article (Journal)
Additional Information: 5731/13889
Uncontrolled Keywords: p53; Phosphorylation; p53 resistance; Nutlin-3; RITA; Apoptosis
Subjects: R Medicine > RB Pathology
Kulliyyahs/Centres/Divisions/Institutes: Kulliyyah of Dentistry
Depositing User: Dr. Solachuddin J.A. Ichwan
Date Deposited: 09 May 2012 10:23
Last Modified: 17 Jul 2014 09:57
URI: http://irep.iium.edu.my/id/eprint/13889

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