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Inhibition of GABA(A) receptors in intestinal stem cells prevents chemoradiotherapy-induced intestinal toxicity
Lethal intestinal tissue toxicity is a common side effect and a dose-limiting factor in chemoradiotherapy. Chemoradiotherapy can trigger DNA damage and induce P53-dependent apoptosis in LGR5(+) intestinal stem cells (ISCs). Gamma-aminobutyric acid (GABA) and its A receptors (GABA(A)R) are present in...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499828/ https://www.ncbi.nlm.nih.gov/pubmed/36125780 http://dx.doi.org/10.1084/jem.20220541 |
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author | Zhang, Cuiyu Zhou, Yuping Zheng, Junjie Ning, Nannan Liu, Haining Jiang, Wenyang Yu, Xin Mu, Kun Li, Yan Guo, Wei Hu, Huili Li, Jingxin Chen, Dawei |
author_facet | Zhang, Cuiyu Zhou, Yuping Zheng, Junjie Ning, Nannan Liu, Haining Jiang, Wenyang Yu, Xin Mu, Kun Li, Yan Guo, Wei Hu, Huili Li, Jingxin Chen, Dawei |
author_sort | Zhang, Cuiyu |
collection | PubMed |
description | Lethal intestinal tissue toxicity is a common side effect and a dose-limiting factor in chemoradiotherapy. Chemoradiotherapy can trigger DNA damage and induce P53-dependent apoptosis in LGR5(+) intestinal stem cells (ISCs). Gamma-aminobutyric acid (GABA) and its A receptors (GABA(A)R) are present in the gastrointestinal tract. However, the functioning of the GABAergic system in ISCs is poorly defined. We found that GABA(A)R α1 (GABRA1) levels increased in the murine intestine after chemoradiotherapy. GABRA1 depletion in LGR5(+) ISCs protected the intestine from chemoradiotherapy-induced P53-dependent apoptosis and prolonged animal survival. The administration of bicuculline, a GABA(A)R antagonist, prevented chemoradiotherapy-induced ISC loss and intestinal damage without reducing the chemoradiosensitivity of tumors. Mechanistically, it was associated with the reduction of reactive oxygen species–induced DNA damage via the L-type voltage–dependent Ca(2+) channels. Notably, flumazenil, a GABA(A)R antagonist approved by the U.S. Food and Drug Administration, rescued human colonic organoids from chemoradiotherapy-induced toxicity. Therefore, flumazenil may be a promising drug for reducing the gastrointestinal side effects of chemoradiotherapy. |
format | Online Article Text |
id | pubmed-9499828 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-94998282023-03-20 Inhibition of GABA(A) receptors in intestinal stem cells prevents chemoradiotherapy-induced intestinal toxicity Zhang, Cuiyu Zhou, Yuping Zheng, Junjie Ning, Nannan Liu, Haining Jiang, Wenyang Yu, Xin Mu, Kun Li, Yan Guo, Wei Hu, Huili Li, Jingxin Chen, Dawei J Exp Med Article Lethal intestinal tissue toxicity is a common side effect and a dose-limiting factor in chemoradiotherapy. Chemoradiotherapy can trigger DNA damage and induce P53-dependent apoptosis in LGR5(+) intestinal stem cells (ISCs). Gamma-aminobutyric acid (GABA) and its A receptors (GABA(A)R) are present in the gastrointestinal tract. However, the functioning of the GABAergic system in ISCs is poorly defined. We found that GABA(A)R α1 (GABRA1) levels increased in the murine intestine after chemoradiotherapy. GABRA1 depletion in LGR5(+) ISCs protected the intestine from chemoradiotherapy-induced P53-dependent apoptosis and prolonged animal survival. The administration of bicuculline, a GABA(A)R antagonist, prevented chemoradiotherapy-induced ISC loss and intestinal damage without reducing the chemoradiosensitivity of tumors. Mechanistically, it was associated with the reduction of reactive oxygen species–induced DNA damage via the L-type voltage–dependent Ca(2+) channels. Notably, flumazenil, a GABA(A)R antagonist approved by the U.S. Food and Drug Administration, rescued human colonic organoids from chemoradiotherapy-induced toxicity. Therefore, flumazenil may be a promising drug for reducing the gastrointestinal side effects of chemoradiotherapy. Rockefeller University Press 2022-09-20 /pmc/articles/PMC9499828/ /pubmed/36125780 http://dx.doi.org/10.1084/jem.20220541 Text en © 2022 Zhang et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Zhang, Cuiyu Zhou, Yuping Zheng, Junjie Ning, Nannan Liu, Haining Jiang, Wenyang Yu, Xin Mu, Kun Li, Yan Guo, Wei Hu, Huili Li, Jingxin Chen, Dawei Inhibition of GABA(A) receptors in intestinal stem cells prevents chemoradiotherapy-induced intestinal toxicity |
title | Inhibition of GABA(A) receptors in intestinal stem cells prevents chemoradiotherapy-induced intestinal toxicity |
title_full | Inhibition of GABA(A) receptors in intestinal stem cells prevents chemoradiotherapy-induced intestinal toxicity |
title_fullStr | Inhibition of GABA(A) receptors in intestinal stem cells prevents chemoradiotherapy-induced intestinal toxicity |
title_full_unstemmed | Inhibition of GABA(A) receptors in intestinal stem cells prevents chemoradiotherapy-induced intestinal toxicity |
title_short | Inhibition of GABA(A) receptors in intestinal stem cells prevents chemoradiotherapy-induced intestinal toxicity |
title_sort | inhibition of gaba(a) receptors in intestinal stem cells prevents chemoradiotherapy-induced intestinal toxicity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499828/ https://www.ncbi.nlm.nih.gov/pubmed/36125780 http://dx.doi.org/10.1084/jem.20220541 |
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