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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...

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Autores principales: Ma, Zikun, Li, Zhiyong, Mao, Yize, Ye, Jingwei, Liu, Zefu, Wang, Yuzhao, Wei, Chen, Cui, Jun, Liu, Zhuowei, Liang, Xiaoyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
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).
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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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