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AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer
The induction of type-I interferons (IFN-Is) is important for the efficacy of chemotherapy. By investigating the role of amino acids in regulation of IFN-I production under chemo-drug treatment in bladder cancer (BC) cells, we find an inherent AhR-dependent negative feedback to restrain STING signal...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10480448/ https://www.ncbi.nlm.nih.gov/pubmed/37670034 http://dx.doi.org/10.1038/s41467-023-41218-5 |
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author | Ma, Zikun Li, Zhiyong Mao, Yize Ye, Jingwei Liu, Zefu Wang, Yuzhao Wei, Chen Cui, Jun Liu, Zhuowei Liang, Xiaoyu |
author_facet | Ma, Zikun Li, Zhiyong Mao, Yize Ye, Jingwei Liu, Zefu Wang, Yuzhao Wei, Chen Cui, Jun Liu, Zhuowei Liang, Xiaoyu |
author_sort | Ma, Zikun |
collection | PubMed |
description | The induction of type-I interferons (IFN-Is) is important for the efficacy of chemotherapy. By investigating the role of amino acids in regulation of IFN-I production under chemo-drug treatment in bladder cancer (BC) cells, we find an inherent AhR-dependent negative feedback to restrain STING signaling and IFN-I production. Mechanistically, in a ligand dependent manner, AhR bridges STING and CUL4B/RBX1 E3 ligase complex, facilitating STING degradation through ubiquitin-proteasome pathway. Inhibition of AhR increases STING levels and reduces tumor growth under cisplatin or STING agonist treatment. Endogenous AhR ligands are mainly consisted of tryptophan (Trp) metabolites; dietary Trp restriction, blocking the key Trp metabolism rate-limiting enzyme IDO1 or inhibition of cellular Trp importation also show similar effect as AhR inhibition. Clinically, BC patients with higher intratumoral expression of AhR or stronger intratumoral Trp metabolism (higher IDO1 or Kyn levels) that lead to higher AhR activation show worse response rate to neoadjuvant chemotherapy (NAC). |
format | Online Article Text |
id | pubmed-10480448 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-104804482023-09-07 AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer Ma, Zikun Li, Zhiyong Mao, Yize Ye, Jingwei Liu, Zefu Wang, Yuzhao Wei, Chen Cui, Jun Liu, Zhuowei Liang, Xiaoyu Nat Commun Article The induction of type-I interferons (IFN-Is) is important for the efficacy of chemotherapy. By investigating the role of amino acids in regulation of IFN-I production under chemo-drug treatment in bladder cancer (BC) cells, we find an inherent AhR-dependent negative feedback to restrain STING signaling and IFN-I production. Mechanistically, in a ligand dependent manner, AhR bridges STING and CUL4B/RBX1 E3 ligase complex, facilitating STING degradation through ubiquitin-proteasome pathway. Inhibition of AhR increases STING levels and reduces tumor growth under cisplatin or STING agonist treatment. Endogenous AhR ligands are mainly consisted of tryptophan (Trp) metabolites; dietary Trp restriction, blocking the key Trp metabolism rate-limiting enzyme IDO1 or inhibition of cellular Trp importation also show similar effect as AhR inhibition. Clinically, BC patients with higher intratumoral expression of AhR or stronger intratumoral Trp metabolism (higher IDO1 or Kyn levels) that lead to higher AhR activation show worse response rate to neoadjuvant chemotherapy (NAC). Nature Publishing Group UK 2023-09-05 /pmc/articles/PMC10480448/ /pubmed/37670034 http://dx.doi.org/10.1038/s41467-023-41218-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Ma, Zikun Li, Zhiyong Mao, Yize Ye, Jingwei Liu, Zefu Wang, Yuzhao Wei, Chen Cui, Jun Liu, Zhuowei Liang, Xiaoyu AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer |
title | AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer |
title_full | AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer |
title_fullStr | AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer |
title_full_unstemmed | AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer |
title_short | AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer |
title_sort | ahr diminishes the efficacy of chemotherapy via suppressing sting dependent type-i interferon in bladder cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10480448/ https://www.ncbi.nlm.nih.gov/pubmed/37670034 http://dx.doi.org/10.1038/s41467-023-41218-5 |
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