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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...

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Autores principales: Tomono, Takumi, Machida, Tatsuya, Kamioka, Hiroki, Shibasaki, Yumi, Yano, Kentaro, Ogihara, Takuo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
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.
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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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