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Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways
The mammalian target of rapamycin (mTOR) functions as two complexes (mTORC1 and mTORC2), regulating cell growth and metabolism. Aberrant mTOR signaling occurs frequently in cancers, so mTOR has become an attractive target for cancer therapy. Iron chelators have emerged as promising anticancer agents...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366895/ https://www.ncbi.nlm.nih.gov/pubmed/32541839 http://dx.doi.org/10.1038/s41388-020-1366-5 |
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author | Shang, Chaowei Zhou, Hongyu Liu, Wang Shen, Tao Luo, Yan Huang, Shile |
author_facet | Shang, Chaowei Zhou, Hongyu Liu, Wang Shen, Tao Luo, Yan Huang, Shile |
author_sort | Shang, Chaowei |
collection | PubMed |
description | The mammalian target of rapamycin (mTOR) functions as two complexes (mTORC1 and mTORC2), regulating cell growth and metabolism. Aberrant mTOR signaling occurs frequently in cancers, so mTOR has become an attractive target for cancer therapy. Iron chelators have emerged as promising anticancer agents. However, the mechanisms underlying the anticancer action of iron chelation are not fully understood. Particularly, reports on the effects of iron chelation on mTOR complexes are inconsistent or controversial. Here, we found that iron chelators consistently inhibited mTORC1 signaling, which was blocked by pretreatment with ferrous sulfate. Mechanistically, iron chelation-induced mTORC1 inhibition was not related to ROS induction, copper chelation, or PP2A activation. Instead, activation of AMPK pathway mainly and activation of both HIF-1/REDD1 and Bnip3 pathways partially contribute to iron chelation-induced mTORC1 inhibition. Our findings indicate that iron chelation inhibits mTORC1 via multiple pathways and iron is essential for mTORC1 activation. |
format | Online Article Text |
id | pubmed-7366895 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73668952020-07-24 Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways Shang, Chaowei Zhou, Hongyu Liu, Wang Shen, Tao Luo, Yan Huang, Shile Oncogene Article The mammalian target of rapamycin (mTOR) functions as two complexes (mTORC1 and mTORC2), regulating cell growth and metabolism. Aberrant mTOR signaling occurs frequently in cancers, so mTOR has become an attractive target for cancer therapy. Iron chelators have emerged as promising anticancer agents. However, the mechanisms underlying the anticancer action of iron chelation are not fully understood. Particularly, reports on the effects of iron chelation on mTOR complexes are inconsistent or controversial. Here, we found that iron chelators consistently inhibited mTORC1 signaling, which was blocked by pretreatment with ferrous sulfate. Mechanistically, iron chelation-induced mTORC1 inhibition was not related to ROS induction, copper chelation, or PP2A activation. Instead, activation of AMPK pathway mainly and activation of both HIF-1/REDD1 and Bnip3 pathways partially contribute to iron chelation-induced mTORC1 inhibition. Our findings indicate that iron chelation inhibits mTORC1 via multiple pathways and iron is essential for mTORC1 activation. Nature Publishing Group UK 2020-06-15 2020 /pmc/articles/PMC7366895/ /pubmed/32541839 http://dx.doi.org/10.1038/s41388-020-1366-5 Text en © The Author(s) 2020 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 Shang, Chaowei Zhou, Hongyu Liu, Wang Shen, Tao Luo, Yan Huang, Shile Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways |
title | Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways |
title_full | Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways |
title_fullStr | Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways |
title_full_unstemmed | Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways |
title_short | Iron chelation inhibits mTORC1 signaling involving activation of AMPK and REDD1/Bnip3 pathways |
title_sort | iron chelation inhibits mtorc1 signaling involving activation of ampk and redd1/bnip3 pathways |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366895/ https://www.ncbi.nlm.nih.gov/pubmed/32541839 http://dx.doi.org/10.1038/s41388-020-1366-5 |
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