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Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade

Dietary methionine interventions are beneficial to apoptosis-inducing chemotherapy and radiotherapy for cancer, while their effects on ferroptosis-targeting therapy and immunotherapy are unknown. Here we show the length of time methionine deprivation affects tumoral ferroptosis differently. Prolonge...

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Autores principales: Xue, Ying, Lu, Fujia, Chang, Zhenzhen, Li, Jing, Gao, Yuan, Zhou, Jie, Luo, Ying, Lai, Yongfeng, Cao, Siyuan, Li, Xiaoxiao, Zhou, Yuhan, Li, Yan, Tan, Zheng, Cheng, Xiang, Li, Xiong, Chen, Jing, Wang, Weimin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10409767/
https://www.ncbi.nlm.nih.gov/pubmed/37553341
http://dx.doi.org/10.1038/s41467-023-40518-0
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author Xue, Ying
Lu, Fujia
Chang, Zhenzhen
Li, Jing
Gao, Yuan
Zhou, Jie
Luo, Ying
Lai, Yongfeng
Cao, Siyuan
Li, Xiaoxiao
Zhou, Yuhan
Li, Yan
Tan, Zheng
Cheng, Xiang
Li, Xiong
Chen, Jing
Wang, Weimin
author_facet Xue, Ying
Lu, Fujia
Chang, Zhenzhen
Li, Jing
Gao, Yuan
Zhou, Jie
Luo, Ying
Lai, Yongfeng
Cao, Siyuan
Li, Xiaoxiao
Zhou, Yuhan
Li, Yan
Tan, Zheng
Cheng, Xiang
Li, Xiong
Chen, Jing
Wang, Weimin
author_sort Xue, Ying
collection PubMed
description Dietary methionine interventions are beneficial to apoptosis-inducing chemotherapy and radiotherapy for cancer, while their effects on ferroptosis-targeting therapy and immunotherapy are unknown. Here we show the length of time methionine deprivation affects tumoral ferroptosis differently. Prolonged methionine deprivation prevents glutathione (GSH) depletion from exceeding the death threshold by blocking cation transport regulator homolog 1 (CHAC1) protein synthesis. Whereas, short-term methionine starvation accelerates ferroptosis by stimulating CHAC1 transcription. In vivo, dietary methionine with intermittent but not sustained deprivation augments tumoral ferroptosis. Intermittent methionine deprivation also sensitizes tumor cells against CD8(+) T cell-mediated cytotoxicity and synergize checkpoint blockade therapy by CHAC1 upregulation. Clinically, tumor CHAC1 correlates with clinical benefits and improved survival in cancer patients treated with checkpoint blockades. Lastly, the triple combination of methionine intermittent deprivation, system x(c)(-) inhibitor and PD-1 blockade shows superior antitumor efficacy. Thus, intermittent methionine deprivation is a promising regimen to target ferroptosis and augment cancer immunotherapy.
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spelling pubmed-104097672023-08-10 Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade Xue, Ying Lu, Fujia Chang, Zhenzhen Li, Jing Gao, Yuan Zhou, Jie Luo, Ying Lai, Yongfeng Cao, Siyuan Li, Xiaoxiao Zhou, Yuhan Li, Yan Tan, Zheng Cheng, Xiang Li, Xiong Chen, Jing Wang, Weimin Nat Commun Article Dietary methionine interventions are beneficial to apoptosis-inducing chemotherapy and radiotherapy for cancer, while their effects on ferroptosis-targeting therapy and immunotherapy are unknown. Here we show the length of time methionine deprivation affects tumoral ferroptosis differently. Prolonged methionine deprivation prevents glutathione (GSH) depletion from exceeding the death threshold by blocking cation transport regulator homolog 1 (CHAC1) protein synthesis. Whereas, short-term methionine starvation accelerates ferroptosis by stimulating CHAC1 transcription. In vivo, dietary methionine with intermittent but not sustained deprivation augments tumoral ferroptosis. Intermittent methionine deprivation also sensitizes tumor cells against CD8(+) T cell-mediated cytotoxicity and synergize checkpoint blockade therapy by CHAC1 upregulation. Clinically, tumor CHAC1 correlates with clinical benefits and improved survival in cancer patients treated with checkpoint blockades. Lastly, the triple combination of methionine intermittent deprivation, system x(c)(-) inhibitor and PD-1 blockade shows superior antitumor efficacy. Thus, intermittent methionine deprivation is a promising regimen to target ferroptosis and augment cancer immunotherapy. Nature Publishing Group UK 2023-08-08 /pmc/articles/PMC10409767/ /pubmed/37553341 http://dx.doi.org/10.1038/s41467-023-40518-0 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
Xue, Ying
Lu, Fujia
Chang, Zhenzhen
Li, Jing
Gao, Yuan
Zhou, Jie
Luo, Ying
Lai, Yongfeng
Cao, Siyuan
Li, Xiaoxiao
Zhou, Yuhan
Li, Yan
Tan, Zheng
Cheng, Xiang
Li, Xiong
Chen, Jing
Wang, Weimin
Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade
title Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade
title_full Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade
title_fullStr Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade
title_full_unstemmed Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade
title_short Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade
title_sort intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10409767/
https://www.ncbi.nlm.nih.gov/pubmed/37553341
http://dx.doi.org/10.1038/s41467-023-40518-0
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