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Notch activator cyclopiazonic acid induces apoptosis in HL-60 cells through calcineurin activation

The Journal of Antibiotics volume 77, pages 30–38 (2024)Cite this article

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Abstract

We screened a library of microbial extracts and compounds library using our constructed assay cells and found pulicatins F (1) and G (2), and cyclopiazonic acid (CPA) (3) as Notch activators. Pulicatin F (1) and (±)-pulicatin G were synthesized and their activities were evaluated. Notch activation of CPA (3) was investigated using Western blot and RT-PCR. CPA (3) increased protein level of HES1 and mRNA expression of HES1. Also, the expression of FMS-like tyrosine kinase 3 (FLT3), which was known to inhibit apoptosis, was also inhibited by CPA (3) addition. The Notch activation by CPA (3) and cytotoxicity against HL-60 were clearly canceled by addition of FK506, which is an inhibitor of calcineurin (CaN). In addition, it was revealed that CPA (3) induced apoptosis in HL-60 cells.

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Acknowledgements

We deeply thank to Prof. Kiyotake Suenaga, Keio University and Prof. Arihiro Iwasaki, Chuo University for measurement of Ca2+ concentration in the cells. This study was supported by a Grant-in-Aid for Scientific Research (B) (21H02639 [MAA]) from the Japan Society for the Promotion of Science (JSPS) and a Grant-in-Aid for Transformative Research Area (A) “Latent Chemical Space” (23H04880 [MAA], 23H04884 [MAA]) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Authors and Affiliations

  1. Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan

    Shiina Suzuki, Shun Saito, Yuki Narushima, Shunta Kodani & Midori A. Arai

  2. Technology Research Association for Next Generation Natural Products Chemistry, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan

    Noritaka Kagaya

  3. National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan

    Hikaru Suenaga & Kazuo Shin-ya

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  1. Shiina Suzuki
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Correspondence to Midori A. Arai.

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Suzuki, S., Saito, S., Narushima, Y. et al. Notch activator cyclopiazonic acid induces apoptosis in HL-60 cells through calcineurin activation. J Antibiot 77, 30–38 (2024). https://doi.org/10.1038/s41429-023-00673-4

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