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Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells
Epithelial-to-mesenchymal transition (EMT) in cancer cells facilitates tumor progression by promoting invasion and metastasis. Snail is a transcriptional factor that induces EMT, while P-glycoprotein (P-gp) is an efflux transporter involved in anticancer drug resistance, and P-gp efflux activity is...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034804/ https://www.ncbi.nlm.nih.gov/pubmed/29979729 http://dx.doi.org/10.1371/journal.pone.0200015 |
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author | Tomono, Takumi Machida, Tatsuya Kamioka, Hiroki Shibasaki, Yumi Yano, Kentaro Ogihara, Takuo |
author_facet | Tomono, Takumi Machida, Tatsuya Kamioka, Hiroki Shibasaki, Yumi Yano, Kentaro Ogihara, Takuo |
author_sort | Tomono, Takumi |
collection | PubMed |
description | Epithelial-to-mesenchymal transition (EMT) in cancer cells facilitates tumor progression by promoting invasion and metastasis. Snail is a transcriptional factor that induces EMT, while P-glycoprotein (P-gp) is an efflux transporter involved in anticancer drug resistance, and P-gp efflux activity is stimulated in Snail-overexpressing lung cancer cells with EMT characteristics. Since the histone deacetylase (HDAC) inhibitor entinostat (Ent) reverses EMT features, our aim in this study was to determine whether Ent also suppresses P-gp activation in Snail-induced cells. First, we confirmed that Ent treatment reduced migration activity, downregulated E-cadherin and upregulated vimentin at the mRNA level in Snail-overexpressing cells, thus inhibiting EMT. Efflux and uptake assays using rhodamine123 (Rho123), a fluorescent P-gp substrate, showed that Ent also inhibited Snail-induced activation of P-gp. Moreover, P-gp activity was more strongly inhibited by Ent in Snail-overexpressing cells than in Mock cells. When we evaluated the uptakes of Rho123 by LLC-PK1 cells and P-gp-overexpressing LLC-GA5COL150 cells, Rho123 accumulation in LLC-GA5COL150 cells was significantly decreased compared with that in LLC-PK1 cells. Coincubation with Ent had no effect on Rho123 accumulation in either of the cell lines. Thus, Ent appears to be an inhibitor, but not a substrate, of P-gp at low concentration. Our results suggest that Ent treatment might suppress not only Snail-induced cancer malignant alteration, but also P-gp-mediated multidrug resistance. |
format | Online Article Text |
id | pubmed-6034804 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-60348042018-07-19 Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells Tomono, Takumi Machida, Tatsuya Kamioka, Hiroki Shibasaki, Yumi Yano, Kentaro Ogihara, Takuo PLoS One Research Article Epithelial-to-mesenchymal transition (EMT) in cancer cells facilitates tumor progression by promoting invasion and metastasis. Snail is a transcriptional factor that induces EMT, while P-glycoprotein (P-gp) is an efflux transporter involved in anticancer drug resistance, and P-gp efflux activity is stimulated in Snail-overexpressing lung cancer cells with EMT characteristics. Since the histone deacetylase (HDAC) inhibitor entinostat (Ent) reverses EMT features, our aim in this study was to determine whether Ent also suppresses P-gp activation in Snail-induced cells. First, we confirmed that Ent treatment reduced migration activity, downregulated E-cadherin and upregulated vimentin at the mRNA level in Snail-overexpressing cells, thus inhibiting EMT. Efflux and uptake assays using rhodamine123 (Rho123), a fluorescent P-gp substrate, showed that Ent also inhibited Snail-induced activation of P-gp. Moreover, P-gp activity was more strongly inhibited by Ent in Snail-overexpressing cells than in Mock cells. When we evaluated the uptakes of Rho123 by LLC-PK1 cells and P-gp-overexpressing LLC-GA5COL150 cells, Rho123 accumulation in LLC-GA5COL150 cells was significantly decreased compared with that in LLC-PK1 cells. Coincubation with Ent had no effect on Rho123 accumulation in either of the cell lines. Thus, Ent appears to be an inhibitor, but not a substrate, of P-gp at low concentration. Our results suggest that Ent treatment might suppress not only Snail-induced cancer malignant alteration, but also P-gp-mediated multidrug resistance. Public Library of Science 2018-07-06 /pmc/articles/PMC6034804/ /pubmed/29979729 http://dx.doi.org/10.1371/journal.pone.0200015 Text en © 2018 Tomono 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 Tomono, Takumi Machida, Tatsuya Kamioka, Hiroki Shibasaki, Yumi Yano, Kentaro Ogihara, Takuo Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells |
title | Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells |
title_full | Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells |
title_fullStr | Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells |
title_full_unstemmed | Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells |
title_short | Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells |
title_sort | entinostat reverses p-glycoprotein activation in snail-overexpressing adenocarcinoma hcc827 cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034804/ https://www.ncbi.nlm.nih.gov/pubmed/29979729 http://dx.doi.org/10.1371/journal.pone.0200015 |
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