Eudistomin C, an Antitumor and Antiviral Natural Product, Targets 40S Ribosome and Inhibits Protein Translation

• Published in: Chembiochem : a European journal of chemical biology Vol. 17; no. 17; pp. 1616 - 1620
• Main Authors: Ota, Yu, Chinen, Takumi, Yoshida, Keisuke, Kudo, Shun, Nagumo, Yoko, Shiwa, Yuh, Yamada, Ryosuke, Umihara, Hirotatsu, Iwasaki, Kotaro, Masumoto, Hiroshi, Yokoshima, Satoshi, Yoshikawa, Hirofumi, Fukuyama, Tohru, Kobayashi, Junichi, Usui, Takeo
• Format: Journal Article
• Language: English
• Published: Germany Blackwell Publishing Ltd 02.09.2016; Wiley Subscription Services, Inc
• Subjects: Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - isolation & purification; Antineoplastic Agents, Phytogenic - pharmacology; Antiviral Agents - chemistry; Antiviral Agents - isolation & purification; Antiviral Agents - pharmacology; Biological Products - chemistry; Biological Products - isolation & purification; Biological Products - pharmacology; Carbolines - chemistry; Carbolines - isolation & purification; Carbolines - pharmacology; Cytotoxicity; eudistomin C; Models, Molecular; Molecular Structure; multidrug sensitive strain; Natural products; Protein Biosynthesis - drug effects; Protein synthesis; protein translation; Proteins; Ribosome Subunits, Small, Eukaryotic - drug effects; uS11; yeast genetics; Yeasts; uS11; eudistomin C; protein translation; yeast genetics; multidrug sensitive strain
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201600075

Eudistomin C (EudiC), a natural product, shows potent antitumor and antiviral activities, but the target molecule and the mechanism of action remain to be revealed. Here, we show that the 40S ribosome is the target in EudiC cytotoxicity. We isolated EudiC‐resistant mutants from a multidrug‐sensitive yeast strain, and a genetic analysis classified these YER (yeast EudiC resistance) mutants into three complementation groups. A genome‐wide study revealed that the YER1‐6 mutation is in the uS11 gene (RPS14A). Biotinylated EudiC pulled down Rps14p‐containing complexes from 40S and 80S ribosomes, but not from the 60S ribosome. EudiC strongly inhibited translation of the wild‐type strain but not of YER1‐6 in cells and in vitro. These results indicate that EudiC is a protein synthesis inhibitor targeting the uS11‐containing ribosomal subunit, and shows cytotoxicity by inhibiting protein translation. Powerful undercurrents: Eudistomin C, a marine natural product, shows potent antitumor and antiviral activities, but the target molecule and the mechanism of action remain to be elucidated. Here, we show that this compound binds to uS11‐containing 40S ribosomal subunit, and achieves cytotoxicity by inhibiting protein translation.