Cargando…
Targeting XBP1-mediated β-catenin expression associated with bladder cancer with newly synthetic Oridonin analogues
Conventional chemotherapy is commonly used for advanced stages of transitional cell carcinoma (TCC) with modest success and high morbidity; however, TCC eventually develops resistance. Muscle invasive bladder cancer (MIBC) is recognized as a lethal disease due to its poor response to traditional che...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302956/ https://www.ncbi.nlm.nih.gov/pubmed/27472396 http://dx.doi.org/10.18632/oncotarget.10863 |
_version_ | 1782506647209377792 |
---|---|
author | Chen, Wei Zhou, Jiancheng Wu, Kaijie Huang, Jun Ding, Ye Yun, Eun-Jin Wang, Bin Ding, Chunyong Hernandez, Elizabeth Santoyo, John Chen, Haiying Lin, Ho Sagalowsky, Arthur He, Dalin Zhou, Jia Hsieh, Jer-Tsong |
author_facet | Chen, Wei Zhou, Jiancheng Wu, Kaijie Huang, Jun Ding, Ye Yun, Eun-Jin Wang, Bin Ding, Chunyong Hernandez, Elizabeth Santoyo, John Chen, Haiying Lin, Ho Sagalowsky, Arthur He, Dalin Zhou, Jia Hsieh, Jer-Tsong |
author_sort | Chen, Wei |
collection | PubMed |
description | Conventional chemotherapy is commonly used for advanced stages of transitional cell carcinoma (TCC) with modest success and high morbidity; however, TCC eventually develops resistance. Muscle invasive bladder cancer (MIBC) is recognized as a lethal disease due to its poor response to traditional chemotherapy. Numerous studies have implicated β-catenin, a critical effector in Wnt–mediated pathway associated with epithelial-mesenchymal transition and cancer stem cell, is involved in TCC progression, and furthermore closely associated with chemo-resistance. In this study, we discovered a novel natural product analogue CYD 6-17 that has a potent inhibitory effect on TCC cells exhibiting drug resistance to various chemotherapeutics, with an IC(50) at nM range. Delivery of CYD 6-17 significantly inhibited the tumor growth using xenograft model but without detectable side effects. Mechanistically, it targeted β-catenin gene transcription by decreasing the binding of XBP1 to the promoter region, which appeared to be a new regulatory mechanism for β-catenin gene expression. Clinically, XBP1 expression correlated with the poor overall survival of patients. Overall, this study unveils unique mechanism of β-catenin gene regulation in advanced TCC and also offers a potential rational therapeutic regimen to MIBC. |
format | Online Article Text |
id | pubmed-5302956 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53029562017-02-13 Targeting XBP1-mediated β-catenin expression associated with bladder cancer with newly synthetic Oridonin analogues Chen, Wei Zhou, Jiancheng Wu, Kaijie Huang, Jun Ding, Ye Yun, Eun-Jin Wang, Bin Ding, Chunyong Hernandez, Elizabeth Santoyo, John Chen, Haiying Lin, Ho Sagalowsky, Arthur He, Dalin Zhou, Jia Hsieh, Jer-Tsong Oncotarget Research Paper Conventional chemotherapy is commonly used for advanced stages of transitional cell carcinoma (TCC) with modest success and high morbidity; however, TCC eventually develops resistance. Muscle invasive bladder cancer (MIBC) is recognized as a lethal disease due to its poor response to traditional chemotherapy. Numerous studies have implicated β-catenin, a critical effector in Wnt–mediated pathway associated with epithelial-mesenchymal transition and cancer stem cell, is involved in TCC progression, and furthermore closely associated with chemo-resistance. In this study, we discovered a novel natural product analogue CYD 6-17 that has a potent inhibitory effect on TCC cells exhibiting drug resistance to various chemotherapeutics, with an IC(50) at nM range. Delivery of CYD 6-17 significantly inhibited the tumor growth using xenograft model but without detectable side effects. Mechanistically, it targeted β-catenin gene transcription by decreasing the binding of XBP1 to the promoter region, which appeared to be a new regulatory mechanism for β-catenin gene expression. Clinically, XBP1 expression correlated with the poor overall survival of patients. Overall, this study unveils unique mechanism of β-catenin gene regulation in advanced TCC and also offers a potential rational therapeutic regimen to MIBC. Impact Journals LLC 2016-07-27 /pmc/articles/PMC5302956/ /pubmed/27472396 http://dx.doi.org/10.18632/oncotarget.10863 Text en Copyright: © 2016 Chen et al. http://creativecommons.org/licenses/by/2.5/ 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 Chen, Wei Zhou, Jiancheng Wu, Kaijie Huang, Jun Ding, Ye Yun, Eun-Jin Wang, Bin Ding, Chunyong Hernandez, Elizabeth Santoyo, John Chen, Haiying Lin, Ho Sagalowsky, Arthur He, Dalin Zhou, Jia Hsieh, Jer-Tsong Targeting XBP1-mediated β-catenin expression associated with bladder cancer with newly synthetic Oridonin analogues |
title | Targeting XBP1-mediated β-catenin expression associated with bladder cancer with newly synthetic Oridonin analogues |
title_full | Targeting XBP1-mediated β-catenin expression associated with bladder cancer with newly synthetic Oridonin analogues |
title_fullStr | Targeting XBP1-mediated β-catenin expression associated with bladder cancer with newly synthetic Oridonin analogues |
title_full_unstemmed | Targeting XBP1-mediated β-catenin expression associated with bladder cancer with newly synthetic Oridonin analogues |
title_short | Targeting XBP1-mediated β-catenin expression associated with bladder cancer with newly synthetic Oridonin analogues |
title_sort | targeting xbp1-mediated β-catenin expression associated with bladder cancer with newly synthetic oridonin analogues |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302956/ https://www.ncbi.nlm.nih.gov/pubmed/27472396 http://dx.doi.org/10.18632/oncotarget.10863 |
work_keys_str_mv | AT chenwei targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT zhoujiancheng targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT wukaijie targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT huangjun targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT dingye targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT yuneunjin targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT wangbin targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT dingchunyong targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT hernandezelizabeth targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT santoyojohn targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT chenhaiying targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT linho targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT sagalowskyarthur targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT hedalin targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT zhoujia targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues AT hsiehjertsong targetingxbp1mediatedbcateninexpressionassociatedwithbladdercancerwithnewlysyntheticoridoninanalogues |