The Notch inhibitor cowanin accelerates nicastrin degradation

Abstract Aberrant activation of Notch signaling contributes to the pathogenesis of several different types of cancer, and Notch pathway inhibitors may have significant therapeutic potential. Using a unique cell-based assay system, we isolated twelve compounds, including one new natural product from...

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Autores principales:	Midori A. Arai, Ryuta Akamine, Anna Tsuchiya, Tatsuro Yoneyama, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b9da3072ca0548b6a685bd903eb53e39
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spelling	oai:doaj.org-article:b9da3072ca0548b6a685bd903eb53e392021-12-02T15:08:26ZThe Notch inhibitor cowanin accelerates nicastrin degradation10.1038/s41598-018-23698-42045-2322https://doaj.org/article/b9da3072ca0548b6a685bd903eb53e392018-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-23698-4https://doaj.org/toc/2045-2322Abstract Aberrant activation of Notch signaling contributes to the pathogenesis of several different types of cancer, and Notch pathway inhibitors may have significant therapeutic potential. Using a unique cell-based assay system, we isolated twelve compounds, including one new natural product from Garcinia speciosa, that inhibit the Notch signaling pathway. HES1 and HES5 are target genes of the Notch cascade, and compound 2, referred to as cowanin, decreased the protein levels of HES1 and HES5 in assay cells. Furthermore, cowanin (2) showed potent cytotoxicity against human leukemic HPB-ALL cells. The Notch signaling inhibitory activity of cowanin (2) is linked to the increased degradation of nicastrin, which is one of the components of the γ-secretase complex. To the best of our knowledge, this is the first example of a compound with Notch pathway inhibitory activity mediated by nicastrin degradation.Midori A. AraiRyuta AkamineAnna TsuchiyaTatsuro YoneyamaTakashi KoyanoThaworn KowithayakornMasami IshibashiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-10 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Midori A. Arai Ryuta Akamine Anna Tsuchiya Tatsuro Yoneyama Takashi Koyano Thaworn Kowithayakorn Masami Ishibashi The Notch inhibitor cowanin accelerates nicastrin degradation
description	Abstract Aberrant activation of Notch signaling contributes to the pathogenesis of several different types of cancer, and Notch pathway inhibitors may have significant therapeutic potential. Using a unique cell-based assay system, we isolated twelve compounds, including one new natural product from Garcinia speciosa, that inhibit the Notch signaling pathway. HES1 and HES5 are target genes of the Notch cascade, and compound 2, referred to as cowanin, decreased the protein levels of HES1 and HES5 in assay cells. Furthermore, cowanin (2) showed potent cytotoxicity against human leukemic HPB-ALL cells. The Notch signaling inhibitory activity of cowanin (2) is linked to the increased degradation of nicastrin, which is one of the components of the γ-secretase complex. To the best of our knowledge, this is the first example of a compound with Notch pathway inhibitory activity mediated by nicastrin degradation.
format	article
author	Midori A. Arai Ryuta Akamine Anna Tsuchiya Tatsuro Yoneyama Takashi Koyano Thaworn Kowithayakorn Masami Ishibashi
author_facet	Midori A. Arai Ryuta Akamine Anna Tsuchiya Tatsuro Yoneyama Takashi Koyano Thaworn Kowithayakorn Masami Ishibashi
author_sort	Midori A. Arai
title	The Notch inhibitor cowanin accelerates nicastrin degradation
title_short	The Notch inhibitor cowanin accelerates nicastrin degradation
title_full	The Notch inhibitor cowanin accelerates nicastrin degradation
title_fullStr	The Notch inhibitor cowanin accelerates nicastrin degradation
title_full_unstemmed	The Notch inhibitor cowanin accelerates nicastrin degradation
title_sort	notch inhibitor cowanin accelerates nicastrin degradation
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/b9da3072ca0548b6a685bd903eb53e39
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The Notch inhibitor cowanin accelerates nicastrin degradation

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