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Yap activation in irradiated parotid salivary glands is regulated by ROCK activity

Radiotherapy plays a major role in the curative treatment of head and neck cancer, either as a single modality therapy, or in combination with surgery or chemotherapy, or both. Despite advances to limit radiation-induced side-effects, the major salivary glands are often affected. This frequently lea...

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Autores principales: Wong, Wen Yu, Gilman, Kristy, Limesand, Kirsten H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644026/
https://www.ncbi.nlm.nih.gov/pubmed/33151927
http://dx.doi.org/10.1371/journal.pone.0232921
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author Wong, Wen Yu
Gilman, Kristy
Limesand, Kirsten H.
author_facet Wong, Wen Yu
Gilman, Kristy
Limesand, Kirsten H.
author_sort Wong, Wen Yu
collection PubMed
description Radiotherapy plays a major role in the curative treatment of head and neck cancer, either as a single modality therapy, or in combination with surgery or chemotherapy, or both. Despite advances to limit radiation-induced side-effects, the major salivary glands are often affected. This frequently leads to hyposalivation which causes an increased risk for xerostomia, dental caries, mucositis, and malnutrition culminating in a significant impact on patients’ quality of life. Previous research demonstrated that loss of salivary function is associated with a decrease in polarity regulators and an increase in nuclear Yap localization in a putative stem and progenitor cell (SPC) population. Yap activation has been shown to be essential for regeneration in intestinal injury models; however, the highest levels of nuclear Yap are observed in irradiated salivary SPCs that do not regenerate the gland. Thus, elucidating the inputs that regulate nuclear Yap localization and determining the role that Yap plays within the entire tissue following radiation damage and during regeneration is critical. In this study, we demonstrate that radiation treatment increases nuclear Yap localization in acinar cells and Yap-regulated genes in parotid salivary tissues. Conversely, administration of insulin-like growth factor 1 (IGF1), known to restore salivary function in mouse models, reduces nuclear Yap localization and Yap transcriptional targets to levels similar to untreated tissues. Activation of Rho-associated protein kinase (ROCK) using calpeptin results in increased Yap-regulated genes in primary acinar cells while inhibition of ROCK activity (Y-27632) leads to decreased Yap transcriptional targets. These results suggest that Yap activity is dependent on ROCK activity and provides new mechanistic insights into the regulation of radiation-induced hyposalivation.
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spelling pubmed-76440262020-11-16 Yap activation in irradiated parotid salivary glands is regulated by ROCK activity Wong, Wen Yu Gilman, Kristy Limesand, Kirsten H. PLoS One Research Article Radiotherapy plays a major role in the curative treatment of head and neck cancer, either as a single modality therapy, or in combination with surgery or chemotherapy, or both. Despite advances to limit radiation-induced side-effects, the major salivary glands are often affected. This frequently leads to hyposalivation which causes an increased risk for xerostomia, dental caries, mucositis, and malnutrition culminating in a significant impact on patients’ quality of life. Previous research demonstrated that loss of salivary function is associated with a decrease in polarity regulators and an increase in nuclear Yap localization in a putative stem and progenitor cell (SPC) population. Yap activation has been shown to be essential for regeneration in intestinal injury models; however, the highest levels of nuclear Yap are observed in irradiated salivary SPCs that do not regenerate the gland. Thus, elucidating the inputs that regulate nuclear Yap localization and determining the role that Yap plays within the entire tissue following radiation damage and during regeneration is critical. In this study, we demonstrate that radiation treatment increases nuclear Yap localization in acinar cells and Yap-regulated genes in parotid salivary tissues. Conversely, administration of insulin-like growth factor 1 (IGF1), known to restore salivary function in mouse models, reduces nuclear Yap localization and Yap transcriptional targets to levels similar to untreated tissues. Activation of Rho-associated protein kinase (ROCK) using calpeptin results in increased Yap-regulated genes in primary acinar cells while inhibition of ROCK activity (Y-27632) leads to decreased Yap transcriptional targets. These results suggest that Yap activity is dependent on ROCK activity and provides new mechanistic insights into the regulation of radiation-induced hyposalivation. Public Library of Science 2020-11-05 /pmc/articles/PMC7644026/ /pubmed/33151927 http://dx.doi.org/10.1371/journal.pone.0232921 Text en © 2020 Wong et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Wong, Wen Yu
Gilman, Kristy
Limesand, Kirsten H.
Yap activation in irradiated parotid salivary glands is regulated by ROCK activity
title Yap activation in irradiated parotid salivary glands is regulated by ROCK activity
title_full Yap activation in irradiated parotid salivary glands is regulated by ROCK activity
title_fullStr Yap activation in irradiated parotid salivary glands is regulated by ROCK activity
title_full_unstemmed Yap activation in irradiated parotid salivary glands is regulated by ROCK activity
title_short Yap activation in irradiated parotid salivary glands is regulated by ROCK activity
title_sort yap activation in irradiated parotid salivary glands is regulated by rock activity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644026/
https://www.ncbi.nlm.nih.gov/pubmed/33151927
http://dx.doi.org/10.1371/journal.pone.0232921
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