TY - JOUR
T1 - The Notch inhibitor cowanin accelerates nicastrin degradation
AU - Arai, Midori A.
AU - Akamine, Ryuta
AU - Tsuchiya, Anna
AU - Yoneyama, Tatsuro
AU - Koyano, Takashi
AU - Kowithayakorn, Thaworn
AU - Ishibashi, Masami
N1 - Funding Information:
This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS), Strategic Priority Research Promotion Program, Chiba University, “Phytochemical Plant Molecular Sciences”, and by a Workshop on Chirality at Chiba University (WCCU). This work was inspired by the international and interdisciplinary environments of the JSPS Core-to-Core Program, “Asian Chemical Biology Initiative”.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-018-23698-4
DO - 10.1038/s41598-018-23698-4
M3 - Article
C2 - 29599482
AN - SCOPUS:85044594141
SN - 2045-2322
VL - 8
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 5376
ER -
