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

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

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 p...

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Main Authors: Teng, Ma, Yamada, Shumpei, Ichwan, Solachuddin J. A., Ohtani, Kiyoshi, Otsu, Megumi, Ikeda, Masa-Aki
Format: Article
Language:English
Published: ELSEVIER 2012
Subjects:
RB Pathology
Online Access:http://irep.iium.edu.my/13889/
http://irep.iium.edu.my/13889/
http://irep.iium.edu.my/13889/
http://irep.iium.edu.my/13889/1/Inability_of_p53-reactivating_compounds_Nutlin-3_and_RITA.pdf
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recordtype eprints
spelling iium-138892014-07-17T01:57:35Z http://irep.iium.edu.my/13889/ Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient for p53Ser46 phosphorylation Teng, Ma Yamada, Shumpei Ichwan, Solachuddin J. A. Ohtani, Kiyoshi Otsu, Megumi Ikeda, Masa-Aki RB Pathology 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. ELSEVIER 2012-01-20 Article PeerReviewed application/pdf en http://irep.iium.edu.my/13889/1/Inability_of_p53-reactivating_compounds_Nutlin-3_and_RITA.pdf 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 http://www.sciencedirect.com/science/article/pii/S0006291X11022029 http://dx.doi.org/10.1016/j.bbrc.2011.11.161
repository_type Digital Repository
institution_category Local University
institution International Islamic University Malaysia
building IIUM Repository
collection Online Access
language English
topic RB Pathology
spellingShingle RB Pathology
Teng, Ma
Yamada, Shumpei
Ichwan, Solachuddin J. A.
Ohtani, Kiyoshi
Otsu, Megumi
Ikeda, Masa-Aki
Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient for p53Ser46 phosphorylation
description 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.
format Article
author Teng, Ma
Yamada, Shumpei
Ichwan, Solachuddin J. A.
Ohtani, Kiyoshi
Otsu, Megumi
Ikeda, Masa-Aki
author_facet Teng, Ma
Yamada, Shumpei
Ichwan, Solachuddin J. A.
Ohtani, Kiyoshi
Otsu, Megumi
Ikeda, Masa-Aki
author_sort Teng, Ma
title Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient for p53Ser46 phosphorylation
title_short Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient for p53Ser46 phosphorylation
title_full Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient for p53Ser46 phosphorylation
title_fullStr Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient for p53Ser46 phosphorylation
title_full_unstemmed Inability of p53-reactivating compounds Nutlin-3 and RITA to overcome p53 resistance in tumor cells deficient for p53Ser46 phosphorylation
title_sort inability of p53-reactivating compounds nutlin-3 and rita to overcome p53 resistance in tumor cells deficient for p53ser46 phosphorylation
publisher ELSEVIER
publishDate 2012
url http://irep.iium.edu.my/13889/
http://irep.iium.edu.my/13889/
http://irep.iium.edu.my/13889/
http://irep.iium.edu.my/13889/1/Inability_of_p53-reactivating_compounds_Nutlin-3_and_RITA.pdf
first_indexed 2023-09-18T20:23:03Z
last_indexed 2023-09-18T20:23:03Z
_version_ 1777408235160993792

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