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Cisplatin-induced ototoxicity in organotypic cochlear cultures occurs independent of gap junctional intercellular communication
Cisplatin is a very effective chemotherapeutic, but severe and permanent hearing loss remains a prevalent side effect. The processes underpinning cisplatin-induced ototoxicity are not well understood. Gap junction channels composed of connexin (Cx) subunits allow for the passage of small molecules a...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214471/ https://www.ncbi.nlm.nih.gov/pubmed/32393745 http://dx.doi.org/10.1038/s41419-020-2551-8 |
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author | Abitbol, Julia Beach, Rianne Barr, Kevin Esseltine, Jessica Allman, Brian Laird, Dale |
author_facet | Abitbol, Julia Beach, Rianne Barr, Kevin Esseltine, Jessica Allman, Brian Laird, Dale |
author_sort | Abitbol, Julia |
collection | PubMed |
description | Cisplatin is a very effective chemotherapeutic, but severe and permanent hearing loss remains a prevalent side effect. The processes underpinning cisplatin-induced ototoxicity are not well understood. Gap junction channels composed of connexin (Cx) subunits allow for the passage of small molecules and ions between contacting neighboring cells. These specialized channels have been postulated to enhance cisplatin-induced cell death by spreading “death signals” throughout the supporting cells of the organ of Corti. This study sought to investigate the role of Cx43 in cisplatin-induced ototoxicity using organotypic cochlear cultures from control and two Cx43-mutant mouse strains harboring either a moderate (Cx43(I130T/+)) or severe (Cx43(G60S/+)) reduction of Cx43 function. Cochlear cultures from Cx43-mutant mice with a severe reduction in Cx43-based gap junctional intercellular communication (GJIC) had an enhanced number of hair cells that were positive for cleaved caspase 3, a marker of active apoptosis, after cisplatin treatment. In cisplatin-treated organotypic cochlear cultures, there was a decrease in the co-localization of Cx26 and Cx30 compared with untreated cultures, suggesting that cisplatin causes reorganization of connexin composition in supporting cells. Both Cx26 and Cx30 protein expression as well as GJIC were decreased in organotypic cochlear cultures treated with the gap-junction blocker carbenoxolone. When cisplatin and carbenoxolone were co-administered, there were no differences in hair cell loss compared with cisplatin treatment alone. Using cisplatin-treated control and Cx43-ablated organ of Corti derived HEI-OC1 mouse cells, we found that greatly reducing GJIC led to preferential induction of an ER stress pathway. Taken together, this study strongly suggests that inhibition of GJIC in organ of Corti cells does not lead to differential susceptibility to cisplatin-induced ototoxicity. Although cisplatin causes the same degree of cell death in gap junction competent and incompetent cochlear cells, the engagement of the mitochondrial dysregulation and ER stress differs. |
format | Online Article Text |
id | pubmed-7214471 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-72144712020-05-14 Cisplatin-induced ototoxicity in organotypic cochlear cultures occurs independent of gap junctional intercellular communication Abitbol, Julia Beach, Rianne Barr, Kevin Esseltine, Jessica Allman, Brian Laird, Dale Cell Death Dis Article Cisplatin is a very effective chemotherapeutic, but severe and permanent hearing loss remains a prevalent side effect. The processes underpinning cisplatin-induced ototoxicity are not well understood. Gap junction channels composed of connexin (Cx) subunits allow for the passage of small molecules and ions between contacting neighboring cells. These specialized channels have been postulated to enhance cisplatin-induced cell death by spreading “death signals” throughout the supporting cells of the organ of Corti. This study sought to investigate the role of Cx43 in cisplatin-induced ototoxicity using organotypic cochlear cultures from control and two Cx43-mutant mouse strains harboring either a moderate (Cx43(I130T/+)) or severe (Cx43(G60S/+)) reduction of Cx43 function. Cochlear cultures from Cx43-mutant mice with a severe reduction in Cx43-based gap junctional intercellular communication (GJIC) had an enhanced number of hair cells that were positive for cleaved caspase 3, a marker of active apoptosis, after cisplatin treatment. In cisplatin-treated organotypic cochlear cultures, there was a decrease in the co-localization of Cx26 and Cx30 compared with untreated cultures, suggesting that cisplatin causes reorganization of connexin composition in supporting cells. Both Cx26 and Cx30 protein expression as well as GJIC were decreased in organotypic cochlear cultures treated with the gap-junction blocker carbenoxolone. When cisplatin and carbenoxolone were co-administered, there were no differences in hair cell loss compared with cisplatin treatment alone. Using cisplatin-treated control and Cx43-ablated organ of Corti derived HEI-OC1 mouse cells, we found that greatly reducing GJIC led to preferential induction of an ER stress pathway. Taken together, this study strongly suggests that inhibition of GJIC in organ of Corti cells does not lead to differential susceptibility to cisplatin-induced ototoxicity. Although cisplatin causes the same degree of cell death in gap junction competent and incompetent cochlear cells, the engagement of the mitochondrial dysregulation and ER stress differs. Nature Publishing Group UK 2020-05-11 /pmc/articles/PMC7214471/ /pubmed/32393745 http://dx.doi.org/10.1038/s41419-020-2551-8 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 Abitbol, Julia Beach, Rianne Barr, Kevin Esseltine, Jessica Allman, Brian Laird, Dale Cisplatin-induced ototoxicity in organotypic cochlear cultures occurs independent of gap junctional intercellular communication |
title | Cisplatin-induced ototoxicity in organotypic cochlear cultures occurs independent of gap junctional intercellular communication |
title_full | Cisplatin-induced ototoxicity in organotypic cochlear cultures occurs independent of gap junctional intercellular communication |
title_fullStr | Cisplatin-induced ototoxicity in organotypic cochlear cultures occurs independent of gap junctional intercellular communication |
title_full_unstemmed | Cisplatin-induced ototoxicity in organotypic cochlear cultures occurs independent of gap junctional intercellular communication |
title_short | Cisplatin-induced ototoxicity in organotypic cochlear cultures occurs independent of gap junctional intercellular communication |
title_sort | cisplatin-induced ototoxicity in organotypic cochlear cultures occurs independent of gap junctional intercellular communication |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214471/ https://www.ncbi.nlm.nih.gov/pubmed/32393745 http://dx.doi.org/10.1038/s41419-020-2551-8 |
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