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Paeoniflorin inhibits glioblastoma growth in vivo and in vitro: a role for the Triad3A-dependent ubiquitin proteasome pathway in TLR4 degradation

BACKGROUND: Paeoniflorin, a polyphenolic compound derived from Radix Paeoniae Alba (Paeonia lactiflora), has exhibited anticancer activity in various human cancers, including glioblastoma. However, the mechanisms underlying the effects of this compound have not been fully elucidated. Toll-like recep...

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Autores principales: Wang, Zhaotao, Yu, Guoyong, Liu, Zhi, Zhu, Jianwei, Chen, Chen, Liu, Ru-en, Xu, Ruxiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931203/
https://www.ncbi.nlm.nih.gov/pubmed/29740218
http://dx.doi.org/10.2147/CMAR.S160292
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author Wang, Zhaotao
Yu, Guoyong
Liu, Zhi
Zhu, Jianwei
Chen, Chen
Liu, Ru-en
Xu, Ruxiang
author_facet Wang, Zhaotao
Yu, Guoyong
Liu, Zhi
Zhu, Jianwei
Chen, Chen
Liu, Ru-en
Xu, Ruxiang
author_sort Wang, Zhaotao
collection PubMed
description BACKGROUND: Paeoniflorin, a polyphenolic compound derived from Radix Paeoniae Alba (Paeonia lactiflora), has exhibited anticancer activity in various human cancers, including glioblastoma. However, the mechanisms underlying the effects of this compound have not been fully elucidated. Toll-like receptor 4 (TLR4) plays an important role in the regulation of cancer cell proliferation and progression, and high TLR4 expression in glioblastoma specimens is associated with a poor prognosis. The present study aimed to investigate whether paeoniflorin suppresses glioblastoma via inhibition of TLR4 expression. METHODS: CCK-8 experiments and clone formation assay were performed to detect the cell proliferation. Western blotting was used to analyze protein expression levels. Detection of Triad3A binding with TLR4 was assessed by the immunoprecipitation. Orthotopic xenograft mouse model was used to evaluate the effect of paeoniflorin in vivo. MST was used to analyze the interaction between paeoniflorin and TLR4 protein. RESULTS: In our study, we found that paeoniflorin effectively inhibited glioblastoma growth and suppressed TLR4 protein levels, as well its downstream effectors both in vivo and in vitro. Moreover, when overexpressed TLR4 in glioblastoma abolished the effects of paeoniflorin on cell proliferation, migration, and invasion. Furthermore, we found that paeoniflorin decreased TLR4 protein through ubiquitination proteasome pathway (UPP)-mediated degradation in glioblastoma cells. Mechanistically, paeoniflorin promoted Triad3A to conjugate with TLR4, resulting in degradation. In addition, Triad3A-shRNA abolished paeoniflorin-enhanced UPP-mediated TLR4 degradation. Finally, we found that paeoniflorin could directly bind with TLR4 protein as assessed by MST assay. CONCLUSION: Our study is the first to identify a novel mechanism for the antitumor activity of paeoniflorin, specifically: it decreases tumor growth by directly targeting TLR4 and modulating the TLR4/Triad3A-dependent axis, leading to TLR4 protein degradation and inhibition of glioblastoma cell progression in vitro and in vivo. Our current findings indicate that paeoniflorin is a potential glioblastoma therapeutic agent due to its Triad3A-dependent ubiquitin degradation of TLR4.
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spelling pubmed-59312032018-05-08 Paeoniflorin inhibits glioblastoma growth in vivo and in vitro: a role for the Triad3A-dependent ubiquitin proteasome pathway in TLR4 degradation Wang, Zhaotao Yu, Guoyong Liu, Zhi Zhu, Jianwei Chen, Chen Liu, Ru-en Xu, Ruxiang Cancer Manag Res Original Research BACKGROUND: Paeoniflorin, a polyphenolic compound derived from Radix Paeoniae Alba (Paeonia lactiflora), has exhibited anticancer activity in various human cancers, including glioblastoma. However, the mechanisms underlying the effects of this compound have not been fully elucidated. Toll-like receptor 4 (TLR4) plays an important role in the regulation of cancer cell proliferation and progression, and high TLR4 expression in glioblastoma specimens is associated with a poor prognosis. The present study aimed to investigate whether paeoniflorin suppresses glioblastoma via inhibition of TLR4 expression. METHODS: CCK-8 experiments and clone formation assay were performed to detect the cell proliferation. Western blotting was used to analyze protein expression levels. Detection of Triad3A binding with TLR4 was assessed by the immunoprecipitation. Orthotopic xenograft mouse model was used to evaluate the effect of paeoniflorin in vivo. MST was used to analyze the interaction between paeoniflorin and TLR4 protein. RESULTS: In our study, we found that paeoniflorin effectively inhibited glioblastoma growth and suppressed TLR4 protein levels, as well its downstream effectors both in vivo and in vitro. Moreover, when overexpressed TLR4 in glioblastoma abolished the effects of paeoniflorin on cell proliferation, migration, and invasion. Furthermore, we found that paeoniflorin decreased TLR4 protein through ubiquitination proteasome pathway (UPP)-mediated degradation in glioblastoma cells. Mechanistically, paeoniflorin promoted Triad3A to conjugate with TLR4, resulting in degradation. In addition, Triad3A-shRNA abolished paeoniflorin-enhanced UPP-mediated TLR4 degradation. Finally, we found that paeoniflorin could directly bind with TLR4 protein as assessed by MST assay. CONCLUSION: Our study is the first to identify a novel mechanism for the antitumor activity of paeoniflorin, specifically: it decreases tumor growth by directly targeting TLR4 and modulating the TLR4/Triad3A-dependent axis, leading to TLR4 protein degradation and inhibition of glioblastoma cell progression in vitro and in vivo. Our current findings indicate that paeoniflorin is a potential glioblastoma therapeutic agent due to its Triad3A-dependent ubiquitin degradation of TLR4. Dove Medical Press 2018-04-27 /pmc/articles/PMC5931203/ /pubmed/29740218 http://dx.doi.org/10.2147/CMAR.S160292 Text en © 2018 Wang et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Wang, Zhaotao
Yu, Guoyong
Liu, Zhi
Zhu, Jianwei
Chen, Chen
Liu, Ru-en
Xu, Ruxiang
Paeoniflorin inhibits glioblastoma growth in vivo and in vitro: a role for the Triad3A-dependent ubiquitin proteasome pathway in TLR4 degradation
title Paeoniflorin inhibits glioblastoma growth in vivo and in vitro: a role for the Triad3A-dependent ubiquitin proteasome pathway in TLR4 degradation
title_full Paeoniflorin inhibits glioblastoma growth in vivo and in vitro: a role for the Triad3A-dependent ubiquitin proteasome pathway in TLR4 degradation
title_fullStr Paeoniflorin inhibits glioblastoma growth in vivo and in vitro: a role for the Triad3A-dependent ubiquitin proteasome pathway in TLR4 degradation
title_full_unstemmed Paeoniflorin inhibits glioblastoma growth in vivo and in vitro: a role for the Triad3A-dependent ubiquitin proteasome pathway in TLR4 degradation
title_short Paeoniflorin inhibits glioblastoma growth in vivo and in vitro: a role for the Triad3A-dependent ubiquitin proteasome pathway in TLR4 degradation
title_sort paeoniflorin inhibits glioblastoma growth in vivo and in vitro: a role for the triad3a-dependent ubiquitin proteasome pathway in tlr4 degradation
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931203/
https://www.ncbi.nlm.nih.gov/pubmed/29740218
http://dx.doi.org/10.2147/CMAR.S160292
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