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Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases

The ubiquitin-proteasome system (UPS) plays a central role in various cellular processes through selectively degrading proteins involved in critical cellular functions. Targeting UPS has been validated as a novel strategy for treating human cancer, as inhibitors of the 20S proteasome catalytic activ...

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Autores principales: Zhao, Chong, Chen, Xin, Yang, Changshan, Zang, Dan, Lan, Xiaoying, Liao, Siyan, Zhang, Peiquan, Wu, Jinjie, Li, Xiaofen, Liu, Ningning, Liao, Yuning, Huang, Hongbiao, Shi, Xianping, Jiang, Lili, Liu, Xiuhua, Ping, Q. Dou, Wang, Xuejun, Liu, Jinbao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355152/
https://www.ncbi.nlm.nih.gov/pubmed/28086217
http://dx.doi.org/10.18632/oncotarget.14572
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author Zhao, Chong
Chen, Xin
Yang, Changshan
Zang, Dan
Lan, Xiaoying
Liao, Siyan
Zhang, Peiquan
Wu, Jinjie
Li, Xiaofen
Liu, Ningning
Liao, Yuning
Huang, Hongbiao
Shi, Xianping
Jiang, Lili
Liu, Xiuhua
Ping, Q. Dou
Wang, Xuejun
Liu, Jinbao
author_facet Zhao, Chong
Chen, Xin
Yang, Changshan
Zang, Dan
Lan, Xiaoying
Liao, Siyan
Zhang, Peiquan
Wu, Jinjie
Li, Xiaofen
Liu, Ningning
Liao, Yuning
Huang, Hongbiao
Shi, Xianping
Jiang, Lili
Liu, Xiuhua
Ping, Q. Dou
Wang, Xuejun
Liu, Jinbao
author_sort Zhao, Chong
collection PubMed
description The ubiquitin-proteasome system (UPS) plays a central role in various cellular processes through selectively degrading proteins involved in critical cellular functions. Targeting UPS has been validated as a novel strategy for treating human cancer, as inhibitors of the 20S proteasome catalytic activity are currently in clinical use for treatment of multiple myeloma and other cancers, and the deubiquitinase activity associated with the proteasome is also a valid target for anticancer agents. Recent studies suggested that zinc pyrithione, an FDA-approved antidandruff agent, may have antitumor activity, but the detailed molecular mechanisms remain unclear. Here we report that zinc pyrithione (ZnPT) targets the proteasome-associated DUBs (USP14 and UCHL5) and inhibits their activities, resulting in a rapid accumulation of protein-ubiquitin conjugates, but without inhibiting the proteolytic activities of 20S proteasomes. Furthermore, ZnPT exhibits cytotoxic effects against various cancer cell lines in vitro, selectively kills bone marrow cells from leukemia patients ex vivo, and efficiently inhibits the growth of lung adenocarcinoma cancer cell xenografts in nude mice. This study has identified zinc pyrithione, an FDA-approved pharmacological agent with potential antitumor properties as a proteasomal DUB inhibitor.
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spelling pubmed-53551522017-04-15 Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases Zhao, Chong Chen, Xin Yang, Changshan Zang, Dan Lan, Xiaoying Liao, Siyan Zhang, Peiquan Wu, Jinjie Li, Xiaofen Liu, Ningning Liao, Yuning Huang, Hongbiao Shi, Xianping Jiang, Lili Liu, Xiuhua Ping, Q. Dou Wang, Xuejun Liu, Jinbao Oncotarget Research Paper The ubiquitin-proteasome system (UPS) plays a central role in various cellular processes through selectively degrading proteins involved in critical cellular functions. Targeting UPS has been validated as a novel strategy for treating human cancer, as inhibitors of the 20S proteasome catalytic activity are currently in clinical use for treatment of multiple myeloma and other cancers, and the deubiquitinase activity associated with the proteasome is also a valid target for anticancer agents. Recent studies suggested that zinc pyrithione, an FDA-approved antidandruff agent, may have antitumor activity, but the detailed molecular mechanisms remain unclear. Here we report that zinc pyrithione (ZnPT) targets the proteasome-associated DUBs (USP14 and UCHL5) and inhibits their activities, resulting in a rapid accumulation of protein-ubiquitin conjugates, but without inhibiting the proteolytic activities of 20S proteasomes. Furthermore, ZnPT exhibits cytotoxic effects against various cancer cell lines in vitro, selectively kills bone marrow cells from leukemia patients ex vivo, and efficiently inhibits the growth of lung adenocarcinoma cancer cell xenografts in nude mice. This study has identified zinc pyrithione, an FDA-approved pharmacological agent with potential antitumor properties as a proteasomal DUB inhibitor. Impact Journals LLC 2017-01-10 /pmc/articles/PMC5355152/ /pubmed/28086217 http://dx.doi.org/10.18632/oncotarget.14572 Text en Copyright: © 2017 Zhao et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Zhao, Chong
Chen, Xin
Yang, Changshan
Zang, Dan
Lan, Xiaoying
Liao, Siyan
Zhang, Peiquan
Wu, Jinjie
Li, Xiaofen
Liu, Ningning
Liao, Yuning
Huang, Hongbiao
Shi, Xianping
Jiang, Lili
Liu, Xiuhua
Ping, Q. Dou
Wang, Xuejun
Liu, Jinbao
Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases
title Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases
title_full Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases
title_fullStr Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases
title_full_unstemmed Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases
title_short Repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases
title_sort repurposing an antidandruff agent to treating cancer: zinc pyrithione inhibits tumor growth via targeting proteasome-associated deubiquitinases
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355152/
https://www.ncbi.nlm.nih.gov/pubmed/28086217
http://dx.doi.org/10.18632/oncotarget.14572
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