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A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPR(ER) axis
Hypoxic tumor microenvironment (TME) plays critical roles in induction of cancer stem cell-like phenotype in breast cancer and contribute to chemoresistance. However, the mechanism underlying stemness reprogramming of breast cancer cells (BCs) by hypoxic TME remains largely unknown. In the present s...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9433403/ https://www.ncbi.nlm.nih.gov/pubmed/35301432 http://dx.doi.org/10.1038/s41418-022-00963-8 |
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author | Yan, Yuanyuan He, Miao Zhao, Lin Wu, Huizhe Zhao, Yanyun Han, Li Wei, Binbin Ye, Dongman Lv, Xuemei Wang, Yan Yao, Weifan Zhao, Haishan Chen, Bo Jin, Zining Wen, Jian Zhu, Yan Yu, Tao Jin, Feng Wei, Minjie |
author_facet | Yan, Yuanyuan He, Miao Zhao, Lin Wu, Huizhe Zhao, Yanyun Han, Li Wei, Binbin Ye, Dongman Lv, Xuemei Wang, Yan Yao, Weifan Zhao, Haishan Chen, Bo Jin, Zining Wen, Jian Zhu, Yan Yu, Tao Jin, Feng Wei, Minjie |
author_sort | Yan, Yuanyuan |
collection | PubMed |
description | Hypoxic tumor microenvironment (TME) plays critical roles in induction of cancer stem cell-like phenotype in breast cancer and contribute to chemoresistance. However, the mechanism underlying stemness reprogramming of breast cancer cells (BCs) by hypoxic TME remains largely unknown. In the present study, we illustrated that HIF-2α, but not HIF-1α, induces stemness in BCs under hypoxia through SOD2-mtROS-PDI/GRP78-UPR(ER) pathway, linking mitochondrial metabolic state to endoplasmic reticulum (ER) response via mitochondrial reactive oxygen species (mtROS) level. HIF-2α activates endoplasmic reticulum unfolded protein response (UPR(ER)) in drug-sensitive MCF7 and T47D cells to induce drug-resistant stem-like phenotype. Genetic depletion or pharmacological inhibition (YQ-0629) of HIF-2α abolished hypoxia-induced stem-like phenotype in vitro and in vivo. Mechanistically, HIF-2α activates transcription of superoxide dismutase 2 (SOD2) under hypoxia and thereby decreases mtROS level. With less mtROS transported to endoplasmic reticulum, the expression and activity of protein disulfide isomerase (PDI) is suppressed, allowing glucose-regulated protein 78 (GRP78) to dissociate from receptor proteins of UPR(ER) and bind misfolded protein to activate UPR(ER), which eventually confer chemoresistance and stem-like properties to BCs. Moreover, the increase in mtROS and PDI levels caused by HIF-2α knockdown and the subsequent UPR(ER) inhibition could be substantially rescued by mitoTEMPOL (a mtROS scavenger), 16F16 (a PDI inhibitor), or GRP78 overexpression. Overall, we reported the critical roles of HIF-2α-SOD2-mtROS-PDI/GRP78-UPR(ER) axis in mediating hypoxia-induced stemness in BCs, highlighting the interaction between organelles and providing evidence for further development of targeted HIF-2α inhibitor as a promising therapeutic strategy for chemoresistant breast cancer. |
format | Online Article Text |
id | pubmed-9433403 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-94334032022-09-02 A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPR(ER) axis Yan, Yuanyuan He, Miao Zhao, Lin Wu, Huizhe Zhao, Yanyun Han, Li Wei, Binbin Ye, Dongman Lv, Xuemei Wang, Yan Yao, Weifan Zhao, Haishan Chen, Bo Jin, Zining Wen, Jian Zhu, Yan Yu, Tao Jin, Feng Wei, Minjie Cell Death Differ Article Hypoxic tumor microenvironment (TME) plays critical roles in induction of cancer stem cell-like phenotype in breast cancer and contribute to chemoresistance. However, the mechanism underlying stemness reprogramming of breast cancer cells (BCs) by hypoxic TME remains largely unknown. In the present study, we illustrated that HIF-2α, but not HIF-1α, induces stemness in BCs under hypoxia through SOD2-mtROS-PDI/GRP78-UPR(ER) pathway, linking mitochondrial metabolic state to endoplasmic reticulum (ER) response via mitochondrial reactive oxygen species (mtROS) level. HIF-2α activates endoplasmic reticulum unfolded protein response (UPR(ER)) in drug-sensitive MCF7 and T47D cells to induce drug-resistant stem-like phenotype. Genetic depletion or pharmacological inhibition (YQ-0629) of HIF-2α abolished hypoxia-induced stem-like phenotype in vitro and in vivo. Mechanistically, HIF-2α activates transcription of superoxide dismutase 2 (SOD2) under hypoxia and thereby decreases mtROS level. With less mtROS transported to endoplasmic reticulum, the expression and activity of protein disulfide isomerase (PDI) is suppressed, allowing glucose-regulated protein 78 (GRP78) to dissociate from receptor proteins of UPR(ER) and bind misfolded protein to activate UPR(ER), which eventually confer chemoresistance and stem-like properties to BCs. Moreover, the increase in mtROS and PDI levels caused by HIF-2α knockdown and the subsequent UPR(ER) inhibition could be substantially rescued by mitoTEMPOL (a mtROS scavenger), 16F16 (a PDI inhibitor), or GRP78 overexpression. Overall, we reported the critical roles of HIF-2α-SOD2-mtROS-PDI/GRP78-UPR(ER) axis in mediating hypoxia-induced stemness in BCs, highlighting the interaction between organelles and providing evidence for further development of targeted HIF-2α inhibitor as a promising therapeutic strategy for chemoresistant breast cancer. Nature Publishing Group UK 2022-03-17 2022-09 /pmc/articles/PMC9433403/ /pubmed/35301432 http://dx.doi.org/10.1038/s41418-022-00963-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Yan, Yuanyuan He, Miao Zhao, Lin Wu, Huizhe Zhao, Yanyun Han, Li Wei, Binbin Ye, Dongman Lv, Xuemei Wang, Yan Yao, Weifan Zhao, Haishan Chen, Bo Jin, Zining Wen, Jian Zhu, Yan Yu, Tao Jin, Feng Wei, Minjie A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPR(ER) axis |
title | A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPR(ER) axis |
title_full | A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPR(ER) axis |
title_fullStr | A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPR(ER) axis |
title_full_unstemmed | A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPR(ER) axis |
title_short | A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPR(ER) axis |
title_sort | novel hif-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via sod2-mtros-pdi/gpr78-upr(er) axis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9433403/ https://www.ncbi.nlm.nih.gov/pubmed/35301432 http://dx.doi.org/10.1038/s41418-022-00963-8 |
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