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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| creator | Tomono, Takumi Machida, Tatsuya Kamioka, Hiroki Shibasaki, Yumi Yano, Kentaro Ogihara, Takuo |
| 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. |
| doi_str_mv | 10.1371/journal.pone.0200015 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0200015</identifier><identifier>PMID: 29979729</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Accumulation ; Activation ; Adenocarcinoma ; Antineoplastic agents ; Biology and Life Sciences ; Breast cancer ; Cancer ; Cancer research ; Cancer therapies ; Drug resistance ; Drug therapy ; E-cadherin ; Efflux ; Enzyme inhibitors ; Fluorescence ; Gene expression ; Glycoproteins ; Growth factors ; Health aspects ; Histone deacetylase ; Inhibitors ; Kinases ; Laboratories ; Leukemia ; Lung cancer ; Lung diseases ; Medical research ; Medicine and Health Sciences ; Membrane proteins ; Mesenchyme ; Metastases ; Multidrug resistance ; P-Glycoprotein ; Pharmaceutical sciences ; Pharmacological research ; Pharmacy ; Polymerase chain reaction ; Research and analysis methods ; Snail protein ; Substrate inhibition ; Substrates ; Vimentin</subject><ispartof>PloS one, 2018-07, Vol.13 (7), p.e0200015-e0200015</ispartof><rights>COPYRIGHT 2018 Public Library of Science</rights><rights>2018 Tomono et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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.</description><subject>Accumulation</subject><subject>Activation</subject><subject>Adenocarcinoma</subject><subject>Antineoplastic agents</subject><subject>Biology and Life Sciences</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer research</subject><subject>Cancer therapies</subject><subject>Drug resistance</subject><subject>Drug therapy</subject><subject>E-cadherin</subject><subject>Efflux</subject><subject>Enzyme inhibitors</subject><subject>Fluorescence</subject><subject>Gene expression</subject><subject>Glycoproteins</subject><subject>Growth factors</subject><subject>Health aspects</subject><subject>Histone deacetylase</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Leukemia</subject><subject>Lung cancer</subject><subject>Lung 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reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells</title><author>Tomono, Takumi ; Machida, Tatsuya ; Kamioka, Hiroki ; Shibasaki, Yumi ; Yano, Kentaro ; Ogihara, Takuo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-3190fc07715bca74eb78d1fe91f62faa25e59a2e3bdcbfe8750bc6e755b2df5c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Accumulation</topic><topic>Activation</topic><topic>Adenocarcinoma</topic><topic>Antineoplastic agents</topic><topic>Biology and Life Sciences</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer research</topic><topic>Cancer therapies</topic><topic>Drug resistance</topic><topic>Drug therapy</topic><topic>E-cadherin</topic><topic>Efflux</topic><topic>Enzyme inhibitors</topic><topic>Fluorescence</topic><topic>Gene expression</topic><topic>Glycoproteins</topic><topic>Growth factors</topic><topic>Health aspects</topic><topic>Histone deacetylase</topic><topic>Inhibitors</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>Leukemia</topic><topic>Lung cancer</topic><topic>Lung diseases</topic><topic>Medical research</topic><topic>Medicine and Health Sciences</topic><topic>Membrane proteins</topic><topic>Mesenchyme</topic><topic>Metastases</topic><topic>Multidrug resistance</topic><topic>P-Glycoprotein</topic><topic>Pharmaceutical sciences</topic><topic>Pharmacological research</topic><topic>Pharmacy</topic><topic>Polymerase chain reaction</topic><topic>Research and analysis methods</topic><topic>Snail protein</topic><topic>Substrate inhibition</topic><topic>Substrates</topic><topic>Vimentin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tomono, Takumi</creatorcontrib><creatorcontrib>Machida, Tatsuya</creatorcontrib><creatorcontrib>Kamioka, Hiroki</creatorcontrib><creatorcontrib>Shibasaki, 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Aamir</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2018-07-06</date><risdate>2018</risdate><volume>13</volume><issue>7</issue><spage>e0200015</spage><epage>e0200015</epage><pages>e0200015-e0200015</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29979729</pmid><doi>10.1371/journal.pone.0200015</doi><orcidid>https://orcid.org/0000-0001-5197-038X</orcidid><orcidid>https://orcid.org/0000-0002-0741-3727</orcidid><orcidid>https://orcid.org/0000-0001-6758-6702</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Accumulation Activation Adenocarcinoma Antineoplastic agents Biology and Life Sciences Breast cancer Cancer Cancer research Cancer therapies Drug resistance Drug therapy E-cadherin Efflux Enzyme inhibitors Fluorescence Gene expression Glycoproteins Growth factors Health aspects Histone deacetylase Inhibitors Kinases Laboratories Leukemia Lung cancer Lung diseases Medical research Medicine and Health Sciences Membrane proteins Mesenchyme Metastases Multidrug resistance P-Glycoprotein Pharmaceutical sciences Pharmacological research Pharmacy Polymerase chain reaction Research and analysis methods Snail protein Substrate inhibition Substrates Vimentin |
| title | Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-20T17%3A10%3A58IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Entinostat%20reverses%20P-glycoprotein%20activation%20in%20snail-overexpressing%20adenocarcinoma%20HCC827%20cells&rft.jtitle=PloS%20one&rft.au=Tomono,%20Takumi&rft.date=2018-07-06&rft.volume=13&rft.issue=7&rft.spage=e0200015&rft.epage=e0200015&rft.pages=e0200015-e0200015&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0200015&rft_dat=%3Cgale_plos_%3EA545634681%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2065385268&rft_id=info:pmid/29979729&rft_galeid=A545634681&rft_doaj_id=oai_doaj_org_article_28d79b31f9dc4a8fba0f3fd627ea58aa&rfr_iscdi=true |