The Notch inhibitor cowanin accelerates nicastrin degradation

Midori A. Arai, Ryuta Akamine, Anna Tsuchiya, Tatsuro Yoneyama, Takashi Koyano, Thaworn Kowithayakorn, Masami Ishibashi

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Article number5376
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1
Externally publishedYes

ASJC Scopus subject areas

  • General

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    Arai, M. A., Akamine, R., Tsuchiya, A., Yoneyama, T., Koyano, T., Kowithayakorn, T., & Ishibashi, M. (2018). The Notch inhibitor cowanin accelerates nicastrin degradation. Scientific reports, 8(1), [5376]. https://doi.org/10.1038/s41598-018-23698-4