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Wild type p53 function in p53(Y220C) mutant harboring cells by treatment with Ashwagandha derived anticancer withanolides: bioinformatics and experimental evidence

BACKGROUND: Tumor suppressor p53 protein is frequently mutated in a large majority of cancers. These mutations induce local or global changes in protein structure thereby affecting its binding to DNA. The structural differences between the wild type and mutant p53 thus provide an opportunity to sele...

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Autores principales: Sundar, Durai, Yu, Yue, Katiyar, Shashank P., Putri, Jayarani F., Dhanjal, Jaspreet Kaur, Wang, Jia, Sari, Anissa Nofita, Kolettas, Evangelos, Kaul, Sunil C., Wadhwa, Renu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390572/
https://www.ncbi.nlm.nih.gov/pubmed/30808373
http://dx.doi.org/10.1186/s13046-019-1099-x
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author Sundar, Durai
Yu, Yue
Katiyar, Shashank P.
Putri, Jayarani F.
Dhanjal, Jaspreet Kaur
Wang, Jia
Sari, Anissa Nofita
Kolettas, Evangelos
Kaul, Sunil C.
Wadhwa, Renu
author_facet Sundar, Durai
Yu, Yue
Katiyar, Shashank P.
Putri, Jayarani F.
Dhanjal, Jaspreet Kaur
Wang, Jia
Sari, Anissa Nofita
Kolettas, Evangelos
Kaul, Sunil C.
Wadhwa, Renu
author_sort Sundar, Durai
collection PubMed
description BACKGROUND: Tumor suppressor p53 protein is frequently mutated in a large majority of cancers. These mutations induce local or global changes in protein structure thereby affecting its binding to DNA. The structural differences between the wild type and mutant p53 thus provide an opportunity to selectively target mutated p53 harboring cancer cells. Restoration of wild type p53 activity in mutants using small molecules that can revert the structural changes have been considered for cancer therapeutics. METHODS: We used bioinformatics and molecular docking tools to investigate the structural changes between the wild type and mutant p53 proteins (p53(V143A), p53(R249S), p53(R273H) and p53(Y220C)) and explored the therapeutic potential of Withaferin A and Withanone for restoration of wild type p53 function in cancer cells. Cancer cells harboring the specific mutant p53 proteins were used for molecular assays to determine the mutant or wild type p53 functions. RESULTS: We found that p53(V143A) mutation does not show any significant structural changes and was also refractory to the binding of withanolides. p53(R249S) mutation critically disturbed the H-bond network and destabilized the DNA binding site. However, withanolides did not show any selective binding to either this mutant or other similar variants. p53(Y220C) mutation created a cavity near the site of mutation with local loss of hydrophobicity and water network, leading to functionally inactive conformation. Mutated structure could accommodate withanolides suggesting their conformational selectivity to target p53(Y220C) mutant. Using human cell lines containing specific p53 mutant proteins, we demonstrated that Withaferin A, Withanone and the extract rich in these withanolides caused restoration of wild type p53 function in mutant p53(Y220C) cells. This was associated with induction of p21(WAF-1)-mediated growth arrest/apoptosis. CONCLUSION: The study suggested that withanolides may serve as highly potent anticancer compounds for treatment of cancers harboring a p53(Y220C) mutation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1099-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-63905722019-03-11 Wild type p53 function in p53(Y220C) mutant harboring cells by treatment with Ashwagandha derived anticancer withanolides: bioinformatics and experimental evidence Sundar, Durai Yu, Yue Katiyar, Shashank P. Putri, Jayarani F. Dhanjal, Jaspreet Kaur Wang, Jia Sari, Anissa Nofita Kolettas, Evangelos Kaul, Sunil C. Wadhwa, Renu J Exp Clin Cancer Res Research BACKGROUND: Tumor suppressor p53 protein is frequently mutated in a large majority of cancers. These mutations induce local or global changes in protein structure thereby affecting its binding to DNA. The structural differences between the wild type and mutant p53 thus provide an opportunity to selectively target mutated p53 harboring cancer cells. Restoration of wild type p53 activity in mutants using small molecules that can revert the structural changes have been considered for cancer therapeutics. METHODS: We used bioinformatics and molecular docking tools to investigate the structural changes between the wild type and mutant p53 proteins (p53(V143A), p53(R249S), p53(R273H) and p53(Y220C)) and explored the therapeutic potential of Withaferin A and Withanone for restoration of wild type p53 function in cancer cells. Cancer cells harboring the specific mutant p53 proteins were used for molecular assays to determine the mutant or wild type p53 functions. RESULTS: We found that p53(V143A) mutation does not show any significant structural changes and was also refractory to the binding of withanolides. p53(R249S) mutation critically disturbed the H-bond network and destabilized the DNA binding site. However, withanolides did not show any selective binding to either this mutant or other similar variants. p53(Y220C) mutation created a cavity near the site of mutation with local loss of hydrophobicity and water network, leading to functionally inactive conformation. Mutated structure could accommodate withanolides suggesting their conformational selectivity to target p53(Y220C) mutant. Using human cell lines containing specific p53 mutant proteins, we demonstrated that Withaferin A, Withanone and the extract rich in these withanolides caused restoration of wild type p53 function in mutant p53(Y220C) cells. This was associated with induction of p21(WAF-1)-mediated growth arrest/apoptosis. CONCLUSION: The study suggested that withanolides may serve as highly potent anticancer compounds for treatment of cancers harboring a p53(Y220C) mutation. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1099-x) contains supplementary material, which is available to authorized users. BioMed Central 2019-02-26 /pmc/articles/PMC6390572/ /pubmed/30808373 http://dx.doi.org/10.1186/s13046-019-1099-x Text en © The Author(s). 2019 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
Sundar, Durai
Yu, Yue
Katiyar, Shashank P.
Putri, Jayarani F.
Dhanjal, Jaspreet Kaur
Wang, Jia
Sari, Anissa Nofita
Kolettas, Evangelos
Kaul, Sunil C.
Wadhwa, Renu
Wild type p53 function in p53(Y220C) mutant harboring cells by treatment with Ashwagandha derived anticancer withanolides: bioinformatics and experimental evidence
title Wild type p53 function in p53(Y220C) mutant harboring cells by treatment with Ashwagandha derived anticancer withanolides: bioinformatics and experimental evidence
title_full Wild type p53 function in p53(Y220C) mutant harboring cells by treatment with Ashwagandha derived anticancer withanolides: bioinformatics and experimental evidence
title_fullStr Wild type p53 function in p53(Y220C) mutant harboring cells by treatment with Ashwagandha derived anticancer withanolides: bioinformatics and experimental evidence
title_full_unstemmed Wild type p53 function in p53(Y220C) mutant harboring cells by treatment with Ashwagandha derived anticancer withanolides: bioinformatics and experimental evidence
title_short Wild type p53 function in p53(Y220C) mutant harboring cells by treatment with Ashwagandha derived anticancer withanolides: bioinformatics and experimental evidence
title_sort wild type p53 function in p53(y220c) mutant harboring cells by treatment with ashwagandha derived anticancer withanolides: bioinformatics and experimental evidence
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390572/
https://www.ncbi.nlm.nih.gov/pubmed/30808373
http://dx.doi.org/10.1186/s13046-019-1099-x
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