Antitumor Activity of Ohmyungsamycin A through the Regulation of the Skp2-p27 Axis and MCM4 in Human Colorectal Cancer Cells

• Published in: Journal of natural products (Washington, D.C.) Vol. 83; no. 1; pp. 118 - 126
• Main Authors: Byun, Woong Sub, Kim, Sunghwa, Shin, Yern-Hyerk, Kim, Won Kyung, Oh, Dong-Chan, Lee, Sang Kook
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society and American Society of Pharmacognosy 24.01.2020
• Subjects: Animals; Apoptosis; Cell Cycle; Cell Cycle Checkpoints - drug effects; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - pharmacology; Humans; Mice; Minichromosome Maintenance Complex Component 4 - genetics; Minichromosome Maintenance Complex Component 4 - metabolism; Molecular Structure; Peptides, Cyclic - chemistry; Peptides, Cyclic - metabolism; Peptides, Cyclic - pharmacology; S-Phase Kinase-Associated Proteins - chemistry; S-Phase Kinase-Associated Proteins - genetics; S-Phase Kinase-Associated Proteins - metabolism; Up-Regulation
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.9b00918

Ohmyungsamycin A (1), a novel cyclic peptide discovered from a marine Streptomyces sp., was previously reported with antibacterial and anticancer activities. However, the antitumor activities and the underlying molecular mechanisms of 1 remain to be elucidated. Compound 1 inhibited the proliferation and tumor growth of HCT116 human colorectal cancer cells based on both in vitro cell cultures and an in vivo animal model. A cDNA microarray analysis revealed that 1 downregulated genes involved in cell cycle checkpoint control. Compound 1 also induced G0/G1 cell cycle arrest that was mediated by the regulation of S-phase kinase-associated protein 2 (Skp2)-p27 axis and minichromosome maintenance protein 4 (MCM4). Furthermore, a longer exposure of 1 exhibited an accumulation of a sub-G1 phase cell population, which is characteristic of apoptotic cells. The induction of apoptosis by 1 was also associated with the modulation of caspase family proteins. Compound 1 effectively suppressed tumor growth in a xenograft mouse model subcutaneously implanted with HCT116 cells. In addition, analysis of tumors revealed that 1 upregulated the expression of the CDK inhibitor p27 but downregulated the expression of Skp2 and MCM4. These findings demonstrate the involvement of 1 in cell cycle regulation and the induction of apoptosis in human colorectal cancer cells.