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Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1α that enhances CoCl(2)-induced doxorubicin resistance in breast cancer cells

Hypoxia inducible factor-1α (HIF-1α) is associated with human breast cancer chemoresistance. Various reports have suggested that multiple pathways are involved in HIF-1α induction and that the molecular mechanisms regulating HIF-1α-induced chemoresistance are still not fully understood. Here, we rep...

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Autores principales: Li, Zheqi, Zhu, Qi, Hu, Lingyun, Chen, Hao, Wu, Zhenghua, Li, Dawei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556394/
https://www.ncbi.nlm.nih.gov/pubmed/26079208
http://dx.doi.org/10.1111/cas.12714
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author Li, Zheqi
Zhu, Qi
Hu, Lingyun
Chen, Hao
Wu, Zhenghua
Li, Dawei
author_facet Li, Zheqi
Zhu, Qi
Hu, Lingyun
Chen, Hao
Wu, Zhenghua
Li, Dawei
author_sort Li, Zheqi
collection PubMed
description Hypoxia inducible factor-1α (HIF-1α) is associated with human breast cancer chemoresistance. Various reports have suggested that multiple pathways are involved in HIF-1α induction and that the molecular mechanisms regulating HIF-1α-induced chemoresistance are still not fully understood. Here, we report that anterior gradient 2 (AGR2), a proposed breast cancer biomarker, is an essential regulator in hypoxia-induced doxorubicin resistance through the binding and stabilization of HIF-1α. Our results show that knockdown of AGR2 in MCF-7 cells leads to the suppression of HIF-1α-induced doxorubicin resistance, whereas elevated levels of AGR2 in MDA-MB-231 cells enhance HIF-1α-induced doxorubicin resistance. AGR2 expression, in turn, is upregulated by the hypoxic induction of HIF-1α at both translational and transcriptional levels via a hypoxia-responsive region from −937 to −912 bp on the AGR2 promoter sequence. By specific binding to HIF-1α, the increased level of intracellular AGR2 stabilizes HIF-1α and delays its proteasomal degradation. Finally, we found that AGR2-stabilized HIF-1α escalates multiple drug resistance protein 1 (MDR1) mRNA levels and limits doxorubicin intake of MCF-7 cells, whereas MCF-7/ADR, a doxorubicin resistant cell line with deficient AGR2 and HIF-1α, acquires wild-type MDR1 overexpression. Our findings, for the first time, describe AGR2 as an important regulator in chemical hypoxia-induced doxorubicin resistance in breast cancer cells, providing a possible explanation for the variable levels of chemoresistance in breast cancers and further validating AGR2 as a potential anti-breast cancer therapeutic target.
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spelling pubmed-45563942015-10-05 Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1α that enhances CoCl(2)-induced doxorubicin resistance in breast cancer cells Li, Zheqi Zhu, Qi Hu, Lingyun Chen, Hao Wu, Zhenghua Li, Dawei Cancer Sci Original Articles Hypoxia inducible factor-1α (HIF-1α) is associated with human breast cancer chemoresistance. Various reports have suggested that multiple pathways are involved in HIF-1α induction and that the molecular mechanisms regulating HIF-1α-induced chemoresistance are still not fully understood. Here, we report that anterior gradient 2 (AGR2), a proposed breast cancer biomarker, is an essential regulator in hypoxia-induced doxorubicin resistance through the binding and stabilization of HIF-1α. Our results show that knockdown of AGR2 in MCF-7 cells leads to the suppression of HIF-1α-induced doxorubicin resistance, whereas elevated levels of AGR2 in MDA-MB-231 cells enhance HIF-1α-induced doxorubicin resistance. AGR2 expression, in turn, is upregulated by the hypoxic induction of HIF-1α at both translational and transcriptional levels via a hypoxia-responsive region from −937 to −912 bp on the AGR2 promoter sequence. By specific binding to HIF-1α, the increased level of intracellular AGR2 stabilizes HIF-1α and delays its proteasomal degradation. Finally, we found that AGR2-stabilized HIF-1α escalates multiple drug resistance protein 1 (MDR1) mRNA levels and limits doxorubicin intake of MCF-7 cells, whereas MCF-7/ADR, a doxorubicin resistant cell line with deficient AGR2 and HIF-1α, acquires wild-type MDR1 overexpression. Our findings, for the first time, describe AGR2 as an important regulator in chemical hypoxia-induced doxorubicin resistance in breast cancer cells, providing a possible explanation for the variable levels of chemoresistance in breast cancers and further validating AGR2 as a potential anti-breast cancer therapeutic target. John Wiley & Sons, Ltd 2015-08 2015-07-17 /pmc/articles/PMC4556394/ /pubmed/26079208 http://dx.doi.org/10.1111/cas.12714 Text en © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Li, Zheqi
Zhu, Qi
Hu, Lingyun
Chen, Hao
Wu, Zhenghua
Li, Dawei
Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1α that enhances CoCl(2)-induced doxorubicin resistance in breast cancer cells
title Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1α that enhances CoCl(2)-induced doxorubicin resistance in breast cancer cells
title_full Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1α that enhances CoCl(2)-induced doxorubicin resistance in breast cancer cells
title_fullStr Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1α that enhances CoCl(2)-induced doxorubicin resistance in breast cancer cells
title_full_unstemmed Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1α that enhances CoCl(2)-induced doxorubicin resistance in breast cancer cells
title_short Anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1α that enhances CoCl(2)-induced doxorubicin resistance in breast cancer cells
title_sort anterior gradient 2 is a binding stabilizer of hypoxia inducible factor-1α that enhances cocl(2)-induced doxorubicin resistance in breast cancer cells
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556394/
https://www.ncbi.nlm.nih.gov/pubmed/26079208
http://dx.doi.org/10.1111/cas.12714
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