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Hinokiflavone Inhibits MDM2 Activity by Targeting the MDM2-MDMX RING Domain

SIMPLE SUMMARY: MDM2 is a ubiquitin E3 ligase, frequently overexpressed in human cancers. A biflavonoid Hinokiflavone was identified by virtual screening to bind the MDM2-MDMX RING domain and inhibit MDM2 E3 ligase activity. Hinokiflavone was shown to downregulate MDM2 and its homolog protein MDMX a...

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Autores principales: Ilic, Viktoria K., Egorova, Olga, Tsang, Ernest, Gatto, Milena, Wen, Yi, Zhao, Yong, Sheng, Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9138535/
https://www.ncbi.nlm.nih.gov/pubmed/35625571
http://dx.doi.org/10.3390/biom12050643
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author Ilic, Viktoria K.
Egorova, Olga
Tsang, Ernest
Gatto, Milena
Wen, Yi
Zhao, Yong
Sheng, Yi
author_facet Ilic, Viktoria K.
Egorova, Olga
Tsang, Ernest
Gatto, Milena
Wen, Yi
Zhao, Yong
Sheng, Yi
author_sort Ilic, Viktoria K.
collection PubMed
description SIMPLE SUMMARY: MDM2 is a ubiquitin E3 ligase, frequently overexpressed in human cancers. A biflavonoid Hinokiflavone was identified by virtual screening to bind the MDM2-MDMX RING domain and inhibit MDM2 E3 ligase activity. Hinokiflavone was shown to downregulate MDM2 and its homolog protein MDMX and inhibit the tumorigenic activity of MDM2 in cancer cells. Hinokiflavone could work as a potential anti-cancer therapeutic agent in malignancies with MDM2 overexpression. ABSTRACT: The proto-oncogene MDM2 is frequently amplified in many human cancers and its overexpression is clinically associated with a poor prognosis. The oncogenic activity of MDM2 is demonstrated by its negative regulation of tumor suppressor p53 and the substrate proteins involved in DNA repair, cell cycle control, and apoptosis pathways. Thus, inhibition of MDM2 activity has been pursued as an attractive direction for the development of anti-cancer therapeutics. Virtual screening was performed using the crystal structure of the MDM2-MDMX RING domain dimer against a natural product library and identified a biflavonoid Hinokiflavone as a promising candidate compound targeting MDM2. Hinokiflavone was shown to bind the MDM2-MDMX RING domain and inhibit MDM2-mediated ubiquitination in vitro. Hinokiflavone treatment resulted in the downregulation of MDM2 and MDMX and induction of apoptosis in various cancer cell lines. Hinokiflavone demonstrated p53-dependent and -independent tumor-suppressive activity. This report provides biochemical and cellular evidence demonstrating the anti-cancer effects of Hinokiflavone through targeting the MDM2-MDMX RING domain.
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spelling pubmed-91385352022-05-28 Hinokiflavone Inhibits MDM2 Activity by Targeting the MDM2-MDMX RING Domain Ilic, Viktoria K. Egorova, Olga Tsang, Ernest Gatto, Milena Wen, Yi Zhao, Yong Sheng, Yi Biomolecules Article SIMPLE SUMMARY: MDM2 is a ubiquitin E3 ligase, frequently overexpressed in human cancers. A biflavonoid Hinokiflavone was identified by virtual screening to bind the MDM2-MDMX RING domain and inhibit MDM2 E3 ligase activity. Hinokiflavone was shown to downregulate MDM2 and its homolog protein MDMX and inhibit the tumorigenic activity of MDM2 in cancer cells. Hinokiflavone could work as a potential anti-cancer therapeutic agent in malignancies with MDM2 overexpression. ABSTRACT: The proto-oncogene MDM2 is frequently amplified in many human cancers and its overexpression is clinically associated with a poor prognosis. The oncogenic activity of MDM2 is demonstrated by its negative regulation of tumor suppressor p53 and the substrate proteins involved in DNA repair, cell cycle control, and apoptosis pathways. Thus, inhibition of MDM2 activity has been pursued as an attractive direction for the development of anti-cancer therapeutics. Virtual screening was performed using the crystal structure of the MDM2-MDMX RING domain dimer against a natural product library and identified a biflavonoid Hinokiflavone as a promising candidate compound targeting MDM2. Hinokiflavone was shown to bind the MDM2-MDMX RING domain and inhibit MDM2-mediated ubiquitination in vitro. Hinokiflavone treatment resulted in the downregulation of MDM2 and MDMX and induction of apoptosis in various cancer cell lines. Hinokiflavone demonstrated p53-dependent and -independent tumor-suppressive activity. This report provides biochemical and cellular evidence demonstrating the anti-cancer effects of Hinokiflavone through targeting the MDM2-MDMX RING domain. MDPI 2022-04-27 /pmc/articles/PMC9138535/ /pubmed/35625571 http://dx.doi.org/10.3390/biom12050643 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ilic, Viktoria K.
Egorova, Olga
Tsang, Ernest
Gatto, Milena
Wen, Yi
Zhao, Yong
Sheng, Yi
Hinokiflavone Inhibits MDM2 Activity by Targeting the MDM2-MDMX RING Domain
title Hinokiflavone Inhibits MDM2 Activity by Targeting the MDM2-MDMX RING Domain
title_full Hinokiflavone Inhibits MDM2 Activity by Targeting the MDM2-MDMX RING Domain
title_fullStr Hinokiflavone Inhibits MDM2 Activity by Targeting the MDM2-MDMX RING Domain
title_full_unstemmed Hinokiflavone Inhibits MDM2 Activity by Targeting the MDM2-MDMX RING Domain
title_short Hinokiflavone Inhibits MDM2 Activity by Targeting the MDM2-MDMX RING Domain
title_sort hinokiflavone inhibits mdm2 activity by targeting the mdm2-mdmx ring domain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9138535/
https://www.ncbi.nlm.nih.gov/pubmed/35625571
http://dx.doi.org/10.3390/biom12050643
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