High content screening identifies monensin as an EMT-selective cytotoxic compound

Abstract Epithelial-to-mesenchymal transition (EMT) is implicated in cancer metastasis and drug resistance. Specifically targeting cancer cells in an EMT-like state may have therapeutic value. In this study, we developed a cell imaging-based high-content screening protocol to identify EMT-selective...

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Autores principales:	Marion Vanneste, Qin Huang, Mengshi Li, Devon Moose, Lei Zhao, Mark A. Stamnes, Michael Schultz, Meng Wu, Michael D. Henry
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/81d4fbdb3f094595b0c61a1302ce2102
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spelling	oai:doaj.org-article:81d4fbdb3f094595b0c61a1302ce21022021-12-02T16:08:04ZHigh content screening identifies monensin as an EMT-selective cytotoxic compound10.1038/s41598-018-38019-y2045-2322https://doaj.org/article/81d4fbdb3f094595b0c61a1302ce21022019-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-38019-yhttps://doaj.org/toc/2045-2322Abstract Epithelial-to-mesenchymal transition (EMT) is implicated in cancer metastasis and drug resistance. Specifically targeting cancer cells in an EMT-like state may have therapeutic value. In this study, we developed a cell imaging-based high-content screening protocol to identify EMT-selective cytotoxic compounds. Among the 2,640 compounds tested, salinomycin and monensin, both monovalent cation ionophores, displayed a potent and selective cytotoxic effect against EMT-like cells. The mechanism of action of monensin was further evaluated. Monensin (10 nM) induced apoptosis, cell cycle arrest, and an increase in reactive oxygen species (ROS) production in TEM 4-18 cells. In addition, monensin rapidly induced swelling of Golgi apparatus and perturbed mitochondrial function. These are previously known effects of monensin, albeit occurring at much higher concentrations in the micromolar range. The cytotoxic effect of monensin was not blocked by inhibitors of ferroptosis. To explore the generality of our findings, we evaluated the toxicity of monensin in 24 human cancer cell lines and classified them as resistant or sensitive based on IC50 cutoff of 100 nM. Gene Set Enrichment Analysis identified EMT as the top enriched gene set in the sensitive group. Importantly, increased monensin sensitivity in EMT-like cells is associated with elevated uptake of 3H-monensin compared to resistant cells.Marion VannesteQin HuangMengshi LiDevon MooseLei ZhaoMark A. StamnesMichael SchultzMeng WuMichael D. HenryNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-15 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marion Vanneste Qin Huang Mengshi Li Devon Moose Lei Zhao Mark A. Stamnes Michael Schultz Meng Wu Michael D. Henry High content screening identifies monensin as an EMT-selective cytotoxic compound
description	Abstract Epithelial-to-mesenchymal transition (EMT) is implicated in cancer metastasis and drug resistance. Specifically targeting cancer cells in an EMT-like state may have therapeutic value. In this study, we developed a cell imaging-based high-content screening protocol to identify EMT-selective cytotoxic compounds. Among the 2,640 compounds tested, salinomycin and monensin, both monovalent cation ionophores, displayed a potent and selective cytotoxic effect against EMT-like cells. The mechanism of action of monensin was further evaluated. Monensin (10 nM) induced apoptosis, cell cycle arrest, and an increase in reactive oxygen species (ROS) production in TEM 4-18 cells. In addition, monensin rapidly induced swelling of Golgi apparatus and perturbed mitochondrial function. These are previously known effects of monensin, albeit occurring at much higher concentrations in the micromolar range. The cytotoxic effect of monensin was not blocked by inhibitors of ferroptosis. To explore the generality of our findings, we evaluated the toxicity of monensin in 24 human cancer cell lines and classified them as resistant or sensitive based on IC50 cutoff of 100 nM. Gene Set Enrichment Analysis identified EMT as the top enriched gene set in the sensitive group. Importantly, increased monensin sensitivity in EMT-like cells is associated with elevated uptake of 3H-monensin compared to resistant cells.
format	article
author	Marion Vanneste Qin Huang Mengshi Li Devon Moose Lei Zhao Mark A. Stamnes Michael Schultz Meng Wu Michael D. Henry
author_facet	Marion Vanneste Qin Huang Mengshi Li Devon Moose Lei Zhao Mark A. Stamnes Michael Schultz Meng Wu Michael D. Henry
author_sort	Marion Vanneste
title	High content screening identifies monensin as an EMT-selective cytotoxic compound
title_short	High content screening identifies monensin as an EMT-selective cytotoxic compound
title_full	High content screening identifies monensin as an EMT-selective cytotoxic compound
title_fullStr	High content screening identifies monensin as an EMT-selective cytotoxic compound
title_full_unstemmed	High content screening identifies monensin as an EMT-selective cytotoxic compound
title_sort	high content screening identifies monensin as an emt-selective cytotoxic compound
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/81d4fbdb3f094595b0c61a1302ce2102
work_keys_str_mv	AT marionvanneste highcontentscreeningidentifiesmonensinasanemtselectivecytotoxiccompound AT qinhuang highcontentscreeningidentifiesmonensinasanemtselectivecytotoxiccompound AT mengshili highcontentscreeningidentifiesmonensinasanemtselectivecytotoxiccompound AT devonmoose highcontentscreeningidentifiesmonensinasanemtselectivecytotoxiccompound AT leizhao highcontentscreeningidentifiesmonensinasanemtselectivecytotoxiccompound AT markastamnes highcontentscreeningidentifiesmonensinasanemtselectivecytotoxiccompound AT michaelschultz highcontentscreeningidentifiesmonensinasanemtselectivecytotoxiccompound AT mengwu highcontentscreeningidentifiesmonensinasanemtselectivecytotoxiccompound AT michaeldhenry highcontentscreeningidentifiesmonensinasanemtselectivecytotoxiccompound
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High content screening identifies monensin as an EMT-selective cytotoxic compound

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