The Notch inhibitor cowanin accelerates nicastrin degradation

被引：23

作者：

Arai, Midori A. ^{[1
]}

Akamine, Ryuta ^{[1
]}

Tsuchiya, Anna ^{[1
]}

Yoneyama, Tatsuro ^{[1
]}

Koyano, Takashi ^{[2
]}

Kowithayakorn, Thaworn ^{[3
]}

Ishibashi, Masami ^{[1
]}

机构：

[1] Chiba Univ, Grad Sch Pharmaceut Sci, Chuo Ku, 1-8-1 Inohana, Chiba 2608675, Japan

[2] Temko Corp, Tokyo, Japan

[3] Khon Kaen Univ, Fac Agr, Khon Kaen, Thailand

来源：

SCIENTIFIC REPORTS | 2018年 / 8卷

基金：

日本学术振兴会;

关键词：

XANTHONES; CANCER; TUMORS;

D O I：

10.1038/s41598-018-23698-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.-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.

引用

页数：10

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