RRC ID 52660
著者 Arai MA, Akamine R, Tsuchiya A, Yoneyama T, Koyano T, Kowithayakorn T, Ishibashi M.
タイトル The Notch inhibitor cowanin accelerates nicastrin degradation.
ジャーナル Sci Rep
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.
巻・号 8(1)
ページ 5376
公開日 2018-3-29
DOI 10.1038/s41598-018-23698-4
PII 10.1038/s41598-018-23698-4
PMID 29599482
PMC PMC5876388
MeSH Amyloid Precursor Protein Secretases / metabolism* Animals Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / metabolism Biological Products / chemistry Biological Products / pharmacology Cell Line, Tumor Cell Survival / drug effects Garcinia / chemistry Garcinia / metabolism HEK293 Cells Humans Membrane Glycoproteins / metabolism* Mice Plasmids / genetics Plasmids / metabolism Receptors, Notch / antagonists & inhibitors Receptors, Notch / genetics Receptors, Notch / metabolism* Repressor Proteins / genetics Repressor Proteins / metabolism Signal Transduction / drug effects Tannins / chemistry Tannins / pharmacology* Transcription Factor HES-1 / genetics Transcription Factor HES-1 / metabolism
IF 3.998
引用数 6
リソース情報
ヒト・動物細胞 HPB-ALL(RCB1935)