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Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer

Estrogen receptor α (ERα) is expressed in ~67% of breast cancers and is critical to their proliferation and progression. The expression of ERα is regarded as a major prognostic marker, making it a meaningful target to treat breast cancer (BCa). However, hormone receptor-positive BCa was sometimes ir...

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Autores principales: Xia, Xiaohong, Liao, Yuning, Guo, Zhiqiang, Li, Yanling, Jiang, Lili, Zhang, Fangcheng, Huang, Chuyi, Liu, Yuan, Wang, Xuejun, Liu, Ningning, Liu, Jinbao, Huang, Hongbiao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155249/
https://www.ncbi.nlm.nih.gov/pubmed/30250021
http://dx.doi.org/10.1038/s41389-018-0086-y
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author Xia, Xiaohong
Liao, Yuning
Guo, Zhiqiang
Li, Yanling
Jiang, Lili
Zhang, Fangcheng
Huang, Chuyi
Liu, Yuan
Wang, Xuejun
Liu, Ningning
Liu, Jinbao
Huang, Hongbiao
author_facet Xia, Xiaohong
Liao, Yuning
Guo, Zhiqiang
Li, Yanling
Jiang, Lili
Zhang, Fangcheng
Huang, Chuyi
Liu, Yuan
Wang, Xuejun
Liu, Ningning
Liu, Jinbao
Huang, Hongbiao
author_sort Xia, Xiaohong
collection PubMed
description Estrogen receptor α (ERα) is expressed in ~67% of breast cancers and is critical to their proliferation and progression. The expression of ERα is regarded as a major prognostic marker, making it a meaningful target to treat breast cancer (BCa). However, hormone receptor-positive BCa was sometimes irresponsive or even resistant to classic anti-hormonal therapies (e.g., fulvestrant and tamoxifen). Hence, novel anti-endocrine therapies are urgent for ERα(+) BCa. A phase II study suggested that bortezomib, an inhibitor blocking the activity of 20 S proteasomes, intervenes in cancer progression for anti-endocrine therapy in BCa. Here we report that proteasome-associated deubiquitinases (USP14 and UCHL5) inhibitors b-AP15 and platinum pyrithione (PtPT) induce growth inhibition in ERα(+) BCa cells. Further studies show that these inhibitors induce cell cycle arrest and apoptosis associated with caspase activation, endoplasmic reticulum (ER) stress and the downregulation of ERα. Moreover, we suggest that b-AP15 and PtPT block ERα signaling via enhancing the ubiquitin-mediated degradation of ERα and inhibiting the transcription of ERα. Collectively, these findings demonstrate that proteasome-associated deubiquitinases inhibitors b-AP15 and PtPT may have the potential to treat BCa resistant to anti-hormonal therapy.
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spelling pubmed-61552492018-09-28 Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer Xia, Xiaohong Liao, Yuning Guo, Zhiqiang Li, Yanling Jiang, Lili Zhang, Fangcheng Huang, Chuyi Liu, Yuan Wang, Xuejun Liu, Ningning Liu, Jinbao Huang, Hongbiao Oncogenesis Article Estrogen receptor α (ERα) is expressed in ~67% of breast cancers and is critical to their proliferation and progression. The expression of ERα is regarded as a major prognostic marker, making it a meaningful target to treat breast cancer (BCa). However, hormone receptor-positive BCa was sometimes irresponsive or even resistant to classic anti-hormonal therapies (e.g., fulvestrant and tamoxifen). Hence, novel anti-endocrine therapies are urgent for ERα(+) BCa. A phase II study suggested that bortezomib, an inhibitor blocking the activity of 20 S proteasomes, intervenes in cancer progression for anti-endocrine therapy in BCa. Here we report that proteasome-associated deubiquitinases (USP14 and UCHL5) inhibitors b-AP15 and platinum pyrithione (PtPT) induce growth inhibition in ERα(+) BCa cells. Further studies show that these inhibitors induce cell cycle arrest and apoptosis associated with caspase activation, endoplasmic reticulum (ER) stress and the downregulation of ERα. Moreover, we suggest that b-AP15 and PtPT block ERα signaling via enhancing the ubiquitin-mediated degradation of ERα and inhibiting the transcription of ERα. Collectively, these findings demonstrate that proteasome-associated deubiquitinases inhibitors b-AP15 and PtPT may have the potential to treat BCa resistant to anti-hormonal therapy. Nature Publishing Group UK 2018-09-24 /pmc/articles/PMC6155249/ /pubmed/30250021 http://dx.doi.org/10.1038/s41389-018-0086-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Xia, Xiaohong
Liao, Yuning
Guo, Zhiqiang
Li, Yanling
Jiang, Lili
Zhang, Fangcheng
Huang, Chuyi
Liu, Yuan
Wang, Xuejun
Liu, Ningning
Liu, Jinbao
Huang, Hongbiao
Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer
title Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer
title_full Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer
title_fullStr Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer
title_full_unstemmed Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer
title_short Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer
title_sort targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155249/
https://www.ncbi.nlm.nih.gov/pubmed/30250021
http://dx.doi.org/10.1038/s41389-018-0086-y
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