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Triptolide, a HSP90 middle domain inhibitor, induces apoptosis in triple manner

Triptolide (TL) is a potent anti-tumor, anti-inflammatory and immunosuppressive natural compound. Mechanistic studies revealed that TL inhibits tumor growth and triggers programmed cell death. Studies further suggested that TL inhibits heat shock response in cancer cells to induce apoptosis. HSP90β...

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Autores principales: Zhang, Frederick Zhehao, Ho, Derek Hoi-Hang, Wong, Roger Hoi-Fung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976465/
https://www.ncbi.nlm.nih.gov/pubmed/29854279
http://dx.doi.org/10.18632/oncotarget.24737
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author Zhang, Frederick Zhehao
Ho, Derek Hoi-Hang
Wong, Roger Hoi-Fung
author_facet Zhang, Frederick Zhehao
Ho, Derek Hoi-Hang
Wong, Roger Hoi-Fung
author_sort Zhang, Frederick Zhehao
collection PubMed
description Triptolide (TL) is a potent anti-tumor, anti-inflammatory and immunosuppressive natural compound. Mechanistic studies revealed that TL inhibits tumor growth and triggers programmed cell death. Studies further suggested that TL inhibits heat shock response in cancer cells to induce apoptosis. HSP90β is the major component of heat shock response and is overexpressed in different types of cancers. Given almost all identified HSP90β inhibitors are either N or C-terminal inhibitors, small molecules attacking cysteine(s) in the middle domain might represent a new class of inhibitors. In the current study, we showed that TL inhibits HSP90β in triple manner. Characterization suggests that TL inhibits ATPase activity by preventing ATP binding thus blunts the chaperone activity. TL disrupts HSP90β-CDC37 (co-chaperone) complex through middle domain Cys366 of HSP90β and causes kinase client protein degradation. At the cellular level, the TL-mediated decrease in CDK4 protein levels in HeLa cells causes reduced phosphorylation of Rb resulting in cell cycle arrest at the G1 phase. Furthermore, our results demonstrated that TL triggers programmed cell death in an HSP90β-dependent manner as knockdown of HSP90β further sensitized TL-mediated cell cycle arrest and apoptotic effect. Surprisingly, our data showed that TL is the first drug to be reported to induce site-specific phosphorylation of HSP90β to drive apoptosome formation in the early phase of the treatment. In summary, our study established that TL is a novel middle domain HSP90β inhibitor with bi-phasic multi-mechanistic inhibition. The unique regulatory mechanism of TL on HSP90β makes it an effective inhibitor.
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spelling pubmed-59764652018-05-31 Triptolide, a HSP90 middle domain inhibitor, induces apoptosis in triple manner Zhang, Frederick Zhehao Ho, Derek Hoi-Hang Wong, Roger Hoi-Fung Oncotarget Research Paper Triptolide (TL) is a potent anti-tumor, anti-inflammatory and immunosuppressive natural compound. Mechanistic studies revealed that TL inhibits tumor growth and triggers programmed cell death. Studies further suggested that TL inhibits heat shock response in cancer cells to induce apoptosis. HSP90β is the major component of heat shock response and is overexpressed in different types of cancers. Given almost all identified HSP90β inhibitors are either N or C-terminal inhibitors, small molecules attacking cysteine(s) in the middle domain might represent a new class of inhibitors. In the current study, we showed that TL inhibits HSP90β in triple manner. Characterization suggests that TL inhibits ATPase activity by preventing ATP binding thus blunts the chaperone activity. TL disrupts HSP90β-CDC37 (co-chaperone) complex through middle domain Cys366 of HSP90β and causes kinase client protein degradation. At the cellular level, the TL-mediated decrease in CDK4 protein levels in HeLa cells causes reduced phosphorylation of Rb resulting in cell cycle arrest at the G1 phase. Furthermore, our results demonstrated that TL triggers programmed cell death in an HSP90β-dependent manner as knockdown of HSP90β further sensitized TL-mediated cell cycle arrest and apoptotic effect. Surprisingly, our data showed that TL is the first drug to be reported to induce site-specific phosphorylation of HSP90β to drive apoptosome formation in the early phase of the treatment. In summary, our study established that TL is a novel middle domain HSP90β inhibitor with bi-phasic multi-mechanistic inhibition. The unique regulatory mechanism of TL on HSP90β makes it an effective inhibitor. Impact Journals LLC 2018-04-27 /pmc/articles/PMC5976465/ /pubmed/29854279 http://dx.doi.org/10.18632/oncotarget.24737 Text en Copyright: © 2018 Zhang et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Zhang, Frederick Zhehao
Ho, Derek Hoi-Hang
Wong, Roger Hoi-Fung
Triptolide, a HSP90 middle domain inhibitor, induces apoptosis in triple manner
title Triptolide, a HSP90 middle domain inhibitor, induces apoptosis in triple manner
title_full Triptolide, a HSP90 middle domain inhibitor, induces apoptosis in triple manner
title_fullStr Triptolide, a HSP90 middle domain inhibitor, induces apoptosis in triple manner
title_full_unstemmed Triptolide, a HSP90 middle domain inhibitor, induces apoptosis in triple manner
title_short Triptolide, a HSP90 middle domain inhibitor, induces apoptosis in triple manner
title_sort triptolide, a hsp90 middle domain inhibitor, induces apoptosis in triple manner
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976465/
https://www.ncbi.nlm.nih.gov/pubmed/29854279
http://dx.doi.org/10.18632/oncotarget.24737
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