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Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis

Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance...

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Autores principales: Chen, Zhenghu, Wang, Long, Yao, Dayong, Yang, Tianshu, Cao, Wen-Ming, Dou, Jun, Pang, Jonathan C., Guan, Shan, Zhang, Huiyuan, Yu, Yang, Zhao, Yanling, Wang, Yongfeng, Xu, Xin, Shi, Yan, Patel, Roma, Zhang, Hong, Vasudevan, Sanjeev A., Liu, Shangfeng, Yang, Jianhua, Nuchtern, Jed G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171816/
https://www.ncbi.nlm.nih.gov/pubmed/27991505
http://dx.doi.org/10.1038/srep38011
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author Chen, Zhenghu
Wang, Long
Yao, Dayong
Yang, Tianshu
Cao, Wen-Ming
Dou, Jun
Pang, Jonathan C.
Guan, Shan
Zhang, Huiyuan
Yu, Yang
Zhao, Yanling
Wang, Yongfeng
Xu, Xin
Shi, Yan
Patel, Roma
Zhang, Hong
Vasudevan, Sanjeev A.
Liu, Shangfeng
Yang, Jianhua
Nuchtern, Jed G.
author_facet Chen, Zhenghu
Wang, Long
Yao, Dayong
Yang, Tianshu
Cao, Wen-Ming
Dou, Jun
Pang, Jonathan C.
Guan, Shan
Zhang, Huiyuan
Yu, Yang
Zhao, Yanling
Wang, Yongfeng
Xu, Xin
Shi, Yan
Patel, Roma
Zhang, Hong
Vasudevan, Sanjeev A.
Liu, Shangfeng
Yang, Jianhua
Nuchtern, Jed G.
author_sort Chen, Zhenghu
collection PubMed
description Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53’s tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53-dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner.
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spelling pubmed-51718162016-12-28 Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis Chen, Zhenghu Wang, Long Yao, Dayong Yang, Tianshu Cao, Wen-Ming Dou, Jun Pang, Jonathan C. Guan, Shan Zhang, Huiyuan Yu, Yang Zhao, Yanling Wang, Yongfeng Xu, Xin Shi, Yan Patel, Roma Zhang, Hong Vasudevan, Sanjeev A. Liu, Shangfeng Yang, Jianhua Nuchtern, Jed G. Sci Rep Article Neuroblastoma (NB) is the most common extracranial tumor in children. Unlike in most adult tumors, tumor suppressor protein 53 (p53) mutations occur with a relatively low frequency in NB and the downstream function of p53 is intact in NB cell lines. Wip1 is a negative regulator of p53 and hindrance of Wip1 activity by novel inhibitor GSK2830371 is a potential strategy to activate p53’s tumor suppressing function in NB. Yet, the in vivo efficacy and the possible mechanisms of GSK2830371 in NB have not yet been elucidated. Here we report that novel Wip1 inhibitor GSK2830371 induced Chk2/p53-mediated apoptosis in NB cells in a p53-dependent manner. In addition, GSK2830371 suppressed the colony-formation potential of p53 wild-type NB cell lines. Furthermore, GSK2830371 enhanced doxorubicin- (Dox) and etoposide- (VP-16) induced cytotoxicity in a subset of NB cell lines, including the chemoresistant LA-N-6 cell line. More importantly, GSK2830371 significantly inhibited tumor growth in an orthotopic xenograft NB mouse model by inducing Chk2/p53-mediated apoptosis in vivo. Taken together, this study suggests that GSK2830371 induces Chk2/p53-mediated apoptosis both in vitro and in vivo in a p53 dependent manner. Nature Publishing Group 2016-12-19 /pmc/articles/PMC5171816/ /pubmed/27991505 http://dx.doi.org/10.1038/srep38011 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Chen, Zhenghu
Wang, Long
Yao, Dayong
Yang, Tianshu
Cao, Wen-Ming
Dou, Jun
Pang, Jonathan C.
Guan, Shan
Zhang, Huiyuan
Yu, Yang
Zhao, Yanling
Wang, Yongfeng
Xu, Xin
Shi, Yan
Patel, Roma
Zhang, Hong
Vasudevan, Sanjeev A.
Liu, Shangfeng
Yang, Jianhua
Nuchtern, Jed G.
Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis
title Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis
title_full Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis
title_fullStr Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis
title_full_unstemmed Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis
title_short Wip1 inhibitor GSK2830371 inhibits neuroblastoma growth by inducing Chk2/p53-mediated apoptosis
title_sort wip1 inhibitor gsk2830371 inhibits neuroblastoma growth by inducing chk2/p53-mediated apoptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171816/
https://www.ncbi.nlm.nih.gov/pubmed/27991505
http://dx.doi.org/10.1038/srep38011
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