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

Area of Science:

• Molecular Biology
• Oncology
• Microbiology

Background:

• Myc proto-oncogenes encode transcription factors; c-Myc overexpression is linked to numerous cancers.
• The precise mechanisms by which high c-Myc expression promotes tumor metastasis are not fully understood.
• Antimycin A was previously identified as a c-Myc inhibitor using a custom screening system.

Purpose of the Study:

• To identify novel natural products that inhibit c-Myc transcriptional activity.
• To elucidate the mechanism of action for newly identified c-Myc inhibitors.
• To establish a screening strategy for natural product-based anticancer drug discovery.

Main Methods:

• Screening of approximately 5,600 microbial extracts using a c-Myc transcriptional activity assay.
• Purification of active compounds from a positive microbial extract (Streptomyces sp. RK19-A0402).
• Biochemical assays to determine the mechanism of action, including mitochondrial function, ROS production, and Western blotting for c-Myc phosphorylation and ubiquitination.

Main Results:

• A microbial extract from Streptomyces sp. RK19-A0402 strongly inhibited c-Myc transcriptional activity.
• Purified compounds were identified as structurally similar to oligomycin A and inhibited mitochondrial complex V.
• Compound-induced mitochondrial dysfunction led to reactive oxygen species (ROS) production, activating GSK3α/β, which phosphorylated c-Myc for ubiquitination and degradation.

Conclusions:

• A novel screening strategy successfully identified natural products with c-Myc inhibitory activity.
• The identified compounds act via mitochondrial dysfunction, ROS production, and subsequent c-Myc degradation.
• These findings highlight potential natural product-derived anticancer agents targeting c-Myc.