NSC348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization

Abstract Nucleophosmin (NPM) mutations causing its export from the nucleoli to the cytoplasm are frequent in acute myeloid leukemia (AML). Due to heterooligomerization of wild type NPM with the AML-related mutant, the wild-type becomes misplaced from the nucleoli and its functions are significantly...

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Autores principales:	Markéta Šašinková, Petr Heřman, Aleš Holoubek, Dita Strachotová, Petra Otevřelová, Dana Grebeňová, Kateřina Kuželová, Barbora Brodská
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1b474fa87d0546bcb278d14120b4631c
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spelling	oai:doaj.org-article:1b474fa87d0546bcb278d14120b4631c2021-12-02T14:12:46ZNSC348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization10.1038/s41598-020-80224-12045-2322https://doaj.org/article/1b474fa87d0546bcb278d14120b4631c2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80224-1https://doaj.org/toc/2045-2322Abstract Nucleophosmin (NPM) mutations causing its export from the nucleoli to the cytoplasm are frequent in acute myeloid leukemia (AML). Due to heterooligomerization of wild type NPM with the AML-related mutant, the wild-type becomes misplaced from the nucleoli and its functions are significantly altered. Dissociation of NPM heterooligomers may thus restore the proper localization and function of wild-type NPM. NSC348884 is supposed to act as a potent inhibitor of NPM oligomerization. The effect of NSC348884 on the NPM oligomerization was thoroughly examined by fluorescence lifetime imaging with utilization of FRET and by a set of immunoprecipitation and electrophoretic methods. Leukemia-derived cell lines and primary AML cells as well as cells transfected with fluorescently labeled NPM forms were investigated. Our results clearly demonstrate that NSC348884 does not inhibit formation of NPM oligomers neither in vivo nor in vitro. Instead, we document that NSC348884 cytotoxicity is rather associated with modified cell adhesion signaling. The cytotoxic mechanism of NSC348884 has therefore to be reconsidered.Markéta ŠašinkováPetr HeřmanAleš HoloubekDita StrachotováPetra OtevřelováDana GrebeňováKateřina KuželováBarbora BrodskáNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Markéta Šašinková Petr Heřman Aleš Holoubek Dita Strachotová Petra Otevřelová Dana Grebeňová Kateřina Kuželová Barbora Brodská NSC348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization
description	Abstract Nucleophosmin (NPM) mutations causing its export from the nucleoli to the cytoplasm are frequent in acute myeloid leukemia (AML). Due to heterooligomerization of wild type NPM with the AML-related mutant, the wild-type becomes misplaced from the nucleoli and its functions are significantly altered. Dissociation of NPM heterooligomers may thus restore the proper localization and function of wild-type NPM. NSC348884 is supposed to act as a potent inhibitor of NPM oligomerization. The effect of NSC348884 on the NPM oligomerization was thoroughly examined by fluorescence lifetime imaging with utilization of FRET and by a set of immunoprecipitation and electrophoretic methods. Leukemia-derived cell lines and primary AML cells as well as cells transfected with fluorescently labeled NPM forms were investigated. Our results clearly demonstrate that NSC348884 does not inhibit formation of NPM oligomers neither in vivo nor in vitro. Instead, we document that NSC348884 cytotoxicity is rather associated with modified cell adhesion signaling. The cytotoxic mechanism of NSC348884 has therefore to be reconsidered.
format	article
author	Markéta Šašinková Petr Heřman Aleš Holoubek Dita Strachotová Petra Otevřelová Dana Grebeňová Kateřina Kuželová Barbora Brodská
author_facet	Markéta Šašinková Petr Heřman Aleš Holoubek Dita Strachotová Petra Otevřelová Dana Grebeňová Kateřina Kuželová Barbora Brodská
author_sort	Markéta Šašinková
title	NSC348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization
title_short	NSC348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization
title_full	NSC348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization
title_fullStr	NSC348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization
title_full_unstemmed	NSC348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization
title_sort	nsc348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1b474fa87d0546bcb278d14120b4631c
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NSC348884 cytotoxicity is not mediated by inhibition of nucleophosmin oligomerization

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