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Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function
Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting se...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233319/ https://www.ncbi.nlm.nih.gov/pubmed/34172723 http://dx.doi.org/10.1038/s41467-021-23985-1 |
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author | Palanikumar, L. Karpauskaite, Laura Al-Sayegh, Mohamed Chehade, Ibrahim Alam, Maheen Hassan, Sarah Maity, Debabrata Ali, Liaqat Kalmouni, Mona Hunashal, Yamanappa Ahmed, Jemil Houhou, Tatiana Karapetyan, Shake Falls, Zackary Samudrala, Ram Pasricha, Renu Esposito, Gennaro Afzal, Ahmed J. Hamilton, Andrew D. Kumar, Sunil Magzoub, Mazin |
author_facet | Palanikumar, L. Karpauskaite, Laura Al-Sayegh, Mohamed Chehade, Ibrahim Alam, Maheen Hassan, Sarah Maity, Debabrata Ali, Liaqat Kalmouni, Mona Hunashal, Yamanappa Ahmed, Jemil Houhou, Tatiana Karapetyan, Shake Falls, Zackary Samudrala, Ram Pasricha, Renu Esposito, Gennaro Afzal, Ahmed J. Hamilton, Andrew D. Kumar, Sunil Magzoub, Mazin |
author_sort | Palanikumar, L. |
collection | PubMed |
description | Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer’s disease and type II diabetes, identified a tripyridylamide, ADH-6, that abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53’s transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment effectively shrinks xenografts harboring mutant p53, while exhibiting no toxicity to healthy tissue, thereby substantially prolonging survival. This study demonstrates the successful application of a bona fide small-molecule amyloid inhibitor as a potent anticancer agent. |
format | Online Article Text |
id | pubmed-8233319 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82333192021-07-09 Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function Palanikumar, L. Karpauskaite, Laura Al-Sayegh, Mohamed Chehade, Ibrahim Alam, Maheen Hassan, Sarah Maity, Debabrata Ali, Liaqat Kalmouni, Mona Hunashal, Yamanappa Ahmed, Jemil Houhou, Tatiana Karapetyan, Shake Falls, Zackary Samudrala, Ram Pasricha, Renu Esposito, Gennaro Afzal, Ahmed J. Hamilton, Andrew D. Kumar, Sunil Magzoub, Mazin Nat Commun Article Missense mutations in p53 are severely deleterious and occur in over 50% of all human cancers. The majority of these mutations are located in the inherently unstable DNA-binding domain (DBD), many of which destabilize the domain further and expose its aggregation-prone hydrophobic core, prompting self-assembly of mutant p53 into inactive cytosolic amyloid-like aggregates. Screening an oligopyridylamide library, previously shown to inhibit amyloid formation associated with Alzheimer’s disease and type II diabetes, identified a tripyridylamide, ADH-6, that abrogates self-assembly of the aggregation-nucleating subdomain of mutant p53 DBD. Moreover, ADH-6 targets and dissociates mutant p53 aggregates in human cancer cells, which restores p53’s transcriptional activity, leading to cell cycle arrest and apoptosis. Notably, ADH-6 treatment effectively shrinks xenografts harboring mutant p53, while exhibiting no toxicity to healthy tissue, thereby substantially prolonging survival. This study demonstrates the successful application of a bona fide small-molecule amyloid inhibitor as a potent anticancer agent. Nature Publishing Group UK 2021-06-25 /pmc/articles/PMC8233319/ /pubmed/34172723 http://dx.doi.org/10.1038/s41467-021-23985-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Palanikumar, L. Karpauskaite, Laura Al-Sayegh, Mohamed Chehade, Ibrahim Alam, Maheen Hassan, Sarah Maity, Debabrata Ali, Liaqat Kalmouni, Mona Hunashal, Yamanappa Ahmed, Jemil Houhou, Tatiana Karapetyan, Shake Falls, Zackary Samudrala, Ram Pasricha, Renu Esposito, Gennaro Afzal, Ahmed J. Hamilton, Andrew D. Kumar, Sunil Magzoub, Mazin Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function |
title | Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function |
title_full | Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function |
title_fullStr | Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function |
title_full_unstemmed | Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function |
title_short | Protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function |
title_sort | protein mimetic amyloid inhibitor potently abrogates cancer-associated mutant p53 aggregation and restores tumor suppressor function |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233319/ https://www.ncbi.nlm.nih.gov/pubmed/34172723 http://dx.doi.org/10.1038/s41467-021-23985-1 |
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