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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Ltd
2015
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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. |
format | Online Article Text |
id | pubmed-4556394 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | John Wiley & Sons, Ltd |
record_format | MEDLINE/PubMed |
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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