Novel Notch signaling inhibitor NSI‑1 suppresses nuclear translocation of the Notch intracellular domain

  • Authors:
    • Takaya Shiraishi
    • Masahiro Sakaitani
    • Satoko Otsuguro
    • Katsumi Maenaka
    • Toshiharu Suzuki
    • Tadashi Nakaya
  • View Affiliations

  • Published online on: July 19, 2019     https://doi.org/10.3892/ijmm.2019.4280
  • Pages: 1574-1584
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Abstract

The Notch receptor serves a fundamental role in the regulation of cell fate determination through intracellular signal transmission. Mutation of the Notch receptor results in abnormal active signaling, leading to the development of diseases involving abnormal cell growth, including malignant tumors. Therefore, the Notch signaling pathway is a useful pharmacological target for the treatment of cancer. In the present study, a compound screening system was designed to identify inhibitors of the Notch signaling targeting Notch intracellular domain (NICD). A total of 9,600 compounds were analyzed using the Michigan Cancer Foundation‑7 (MCF7) human breast adenocarcinoma cell line and the SH‑SY5Y human neuroblastoma cell line with the reporter assay system using an artificial protein encoding a partial Notch carboxyl‑terminal fragment fused to the Gal4 DNA‑binding domain. The molecular mechanism underlying the inhibition of Notch signaling by a hit compound was further validated using biochemical and cell biological approaches. Using the screening system, a potential candidate, Notch signaling inhibitor‑1 (NSI‑1), was isolated which showed 50% inhibition at 6.1 µM in an exogenous Notch signaling system. In addition, NSI‑1 suppressed the nuclear translocation of NICD and endogenous gene expression of hairy and enhancer of split‑1, indicating that NSI‑1 specifically targets Notch. Notably, NSI‑1 suppressed the cell viability of MCF7 cells and another human breast adenocarcinoma cell line, MDA‑MB‑231 exhibiting constitutive and high Notch signaling activity, whereas no significant effect was observed in the SH‑SY5Y cells bearing a lower Notch signaling activity. NSI‑1 significantly suppressed the viability of SH‑SY5Y cells expressing exogenous human Notch1. These results indicate that NSI‑1 is a novel Notch signaling inhibitor and suggest its potential as a useful drug for the treatment of diseases induced by constitutively active Notch signaling.

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October 2019
Volume 44 Issue 4

Print ISSN: 1107-3756
Online ISSN:1791-244X

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APA
Shiraishi, T., Sakaitani, M., Otsuguro, S., Maenaka, K., Suzuki, T., & Nakaya, T. (2019). Novel Notch signaling inhibitor NSI‑1 suppresses nuclear translocation of the Notch intracellular domain. International Journal of Molecular Medicine, 44, 1574-1584. https://doi.org/10.3892/ijmm.2019.4280
MLA
Shiraishi, T., Sakaitani, M., Otsuguro, S., Maenaka, K., Suzuki, T., Nakaya, T."Novel Notch signaling inhibitor NSI‑1 suppresses nuclear translocation of the Notch intracellular domain". International Journal of Molecular Medicine 44.4 (2019): 1574-1584.
Chicago
Shiraishi, T., Sakaitani, M., Otsuguro, S., Maenaka, K., Suzuki, T., Nakaya, T."Novel Notch signaling inhibitor NSI‑1 suppresses nuclear translocation of the Notch intracellular domain". International Journal of Molecular Medicine 44, no. 4 (2019): 1574-1584. https://doi.org/10.3892/ijmm.2019.4280