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Reactivation of mutant p53 by capsaicin, the major constituent of peppers

BACKGROUND: Mutations in the p53 oncosuppressor gene are highly frequent in human cancers. These alterations are mainly point mutations in the DNA binding domain of p53 and disable p53 from transactivating target genes devoted to anticancer activity. Mutant p53 proteins are usually more stable than...

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Autores principales: Garufi, Alessia, Pistritto, Giuseppa, Cirone, Mara, D’Orazi, Gabriella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012067/
https://www.ncbi.nlm.nih.gov/pubmed/27599722
http://dx.doi.org/10.1186/s13046-016-0417-9
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author Garufi, Alessia
Pistritto, Giuseppa
Cirone, Mara
D’Orazi, Gabriella
author_facet Garufi, Alessia
Pistritto, Giuseppa
Cirone, Mara
D’Orazi, Gabriella
author_sort Garufi, Alessia
collection PubMed
description BACKGROUND: Mutations in the p53 oncosuppressor gene are highly frequent in human cancers. These alterations are mainly point mutations in the DNA binding domain of p53 and disable p53 from transactivating target genes devoted to anticancer activity. Mutant p53 proteins are usually more stable than wild-type p53 and may not only impair wild-type p53 activity but also acquire pro-oncogenic functions. Therefore, targeting mutant p53 to clear the hyperstable proteins or change p53 conformation to reactivate wild-type p53 protein functions is a powerful anticancer strategy. Several small molecules have been tested for p53 reactivation in mutant p53-carrying cells while studies exploiting the effect of natural compounds are limited. Capsaicin (CPS) is the major constituent of peppers and show antitumor activity by targeting several molecular pathway, however, its effect on mutant p53 reactivation has not been assessed yet. In this study we aimed at investigating whether mutant p53 could be a new target of capsaicin-induced cell death and the underlying mechanisms. METHODS: p53 levels were analysed by western blot upon capsaicin treatment in the presence of the autophagy inhibitor chloroquine. The mutant p53 reactivation was evaluated by chromatin-immunoprecipitation (ChIP) assay and semi-quantitative RT-PCR analyses of wild-type p53 target genes. The specific wild-type p53 activation was determined by using the inhibitor of p53 transactivation function, pifithrin-α and siRNA for p53. RESULTS: Here, we show that capsaicin induced autophagy that was, at least in part, responsible of mutant p53 protein degradation. Abrogation of mutant p53 by capsaicin restored wild-type p53 activities over mutant p53 functions, contributing to cancer cell death. Similar effects were confirmed in cancer cells bearing tumor-associated p53 mutations and in H1299 (p53 null) with overexpressed p53R175H and p53R273H mutant proteins. CONCLUSION: These findings demonstrate for the first time that capsaicin may reduce mutant p53 levels and reactivate wild-type p53 protein in mutant p53-carrying cells and the p53 reactivation contributes to capsaicin-induced cell death.
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spelling pubmed-50120672016-09-07 Reactivation of mutant p53 by capsaicin, the major constituent of peppers Garufi, Alessia Pistritto, Giuseppa Cirone, Mara D’Orazi, Gabriella J Exp Clin Cancer Res Research BACKGROUND: Mutations in the p53 oncosuppressor gene are highly frequent in human cancers. These alterations are mainly point mutations in the DNA binding domain of p53 and disable p53 from transactivating target genes devoted to anticancer activity. Mutant p53 proteins are usually more stable than wild-type p53 and may not only impair wild-type p53 activity but also acquire pro-oncogenic functions. Therefore, targeting mutant p53 to clear the hyperstable proteins or change p53 conformation to reactivate wild-type p53 protein functions is a powerful anticancer strategy. Several small molecules have been tested for p53 reactivation in mutant p53-carrying cells while studies exploiting the effect of natural compounds are limited. Capsaicin (CPS) is the major constituent of peppers and show antitumor activity by targeting several molecular pathway, however, its effect on mutant p53 reactivation has not been assessed yet. In this study we aimed at investigating whether mutant p53 could be a new target of capsaicin-induced cell death and the underlying mechanisms. METHODS: p53 levels were analysed by western blot upon capsaicin treatment in the presence of the autophagy inhibitor chloroquine. The mutant p53 reactivation was evaluated by chromatin-immunoprecipitation (ChIP) assay and semi-quantitative RT-PCR analyses of wild-type p53 target genes. The specific wild-type p53 activation was determined by using the inhibitor of p53 transactivation function, pifithrin-α and siRNA for p53. RESULTS: Here, we show that capsaicin induced autophagy that was, at least in part, responsible of mutant p53 protein degradation. Abrogation of mutant p53 by capsaicin restored wild-type p53 activities over mutant p53 functions, contributing to cancer cell death. Similar effects were confirmed in cancer cells bearing tumor-associated p53 mutations and in H1299 (p53 null) with overexpressed p53R175H and p53R273H mutant proteins. CONCLUSION: These findings demonstrate for the first time that capsaicin may reduce mutant p53 levels and reactivate wild-type p53 protein in mutant p53-carrying cells and the p53 reactivation contributes to capsaicin-induced cell death. BioMed Central 2016-09-06 /pmc/articles/PMC5012067/ /pubmed/27599722 http://dx.doi.org/10.1186/s13046-016-0417-9 Text en © The Author(s). 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Garufi, Alessia
Pistritto, Giuseppa
Cirone, Mara
D’Orazi, Gabriella
Reactivation of mutant p53 by capsaicin, the major constituent of peppers
title Reactivation of mutant p53 by capsaicin, the major constituent of peppers
title_full Reactivation of mutant p53 by capsaicin, the major constituent of peppers
title_fullStr Reactivation of mutant p53 by capsaicin, the major constituent of peppers
title_full_unstemmed Reactivation of mutant p53 by capsaicin, the major constituent of peppers
title_short Reactivation of mutant p53 by capsaicin, the major constituent of peppers
title_sort reactivation of mutant p53 by capsaicin, the major constituent of peppers
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012067/
https://www.ncbi.nlm.nih.gov/pubmed/27599722
http://dx.doi.org/10.1186/s13046-016-0417-9
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