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ARTICLE

Identification of microbial metabolites that accelerate the ubiquitin-dependent degradation of c-Myc

ZIYU LIU^1,2, AKIKO OKANO^3,4, EMIKO SANADA^1,3,4, YUSHI FUTAMURA^3,4, TOSHIHIKO NOGAWA^3,5, KOSUKE ISHIKAWA⁶, KENTARO SEMBA^7,8, JIANG LI⁹, XIAOMENG LI¹⁰, HIROYUKI OSADA^3,4,11,*, NOBUMOTO WATANABE^1,2,4,*

1 Bioprobe Application Research Unit, RIKEN CSRS, Saitama, 351-0198, Japan
2 Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
3 Chemical Biology Research Group, RIKEN CSRS, Saitama, 351-0198, Japan
4 Chemical Resource Development Research Unit, RIKEN CSRS, Saitama, 351-0198, Japan
5 Molecular Structure Characterization Unit, RIKEN CSRS, Saitama, 351-0198, Japan
6 Japan Biological Informatics Consortium (JBIC), Tokyo, 135-8073, Japan
7 Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, 162-8480, Japan
8 Medical-Industrial Translational Research Center, Fukushima Medical University, Fukushima, 960-1295, Japan
9 Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
10 KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China
11 Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan

* Corresponding Authors: HIROYUKI OSADA. Email: ; NOBUMOTO WATANABE. Email:

(This article belongs to the Special Issue: Approach from Chemical Biology for Cancer Research)

Oncology Research 2023, 31(5), 655-666. https://doi.org/10.32604/or.2023.030248

Received 28 March 2023; Accepted 15 June 2023; Issue published 21 July 2023

Abstract

Myc belongs to a family of proto-oncogenes that encode transcription factors. The overexpression of c-Myc causes many types of cancers. Recently, we established a system for screening c-Myc inhibitors and identified antimycin A by screening the RIKEN NPDepo chemical library. The specific mechanism of promoting tumor cell metastasis by high c-Myc expression remains to be explained. In this study, we screened approximately 5,600 microbial extracts using this system and identified a broth prepared from Streptomyces sp. RK19-A0402 strongly inhibits c-Myc transcriptional activity. After purification of the hit broth, we identified compounds closely related to the aglycone of cytovaricin and had a structure similar to that of oligomycin A. Similar to oligomycin A, the hit compounds inhibited mitochondrial complex V. The mitochondria dysfunction caused by the compounds induced the production of reactive oxygen species (ROS), and the ROS activated GSK3α/β that phosphorylated c-Myc for ubiquitination. This study provides a successful screening strategy for identifying natural products as potential c-Myc inhibitors as potential anticancer agents.

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Supplementary Material

Supplementary Material File

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