Chemistry and biology of moverastins, inhibitors of cancer cell migration, produced by Aspergillus.
Cancer cell migration is a required step in cancer metastasis. We screened for inhibitors of cancer cell migration of microbial origin, and obtained moverastin, a member of the cylindrol family, from Aspergillus sp. F7720. However, the results of an NMR spectroscopic analysis raised the possibility that moverastin is a mixture of two diastereomers. Separation of the C-10 epimers of synthetic moverastin and a bioassay revealed that both diastereomers (moverastins A and B) had inhibitory effects on cell migration. Furthermore, we demonstrated that moverastins A and B inhibited FTase in vitro, and they also inhibited both the membrane localization of H-Ras and the activation of the PI3K/Akt pathway in EC17 cells. Thus, moverastins inhibited the migration of tumor cells by inhibiting the farnesylation of H-Ras, and subsequent H-Ras-dependent activation of the PI3K/Akt pathway.
Takemoto
Yasushi
Y
Department of Bioscience and Informatics, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
Watanabe
Hidenori
H
Uchida
Kenji
K
Matsumura
Koji
K
Nakae
Koichi
K
Tashiro
Etsu
E
Shindo
Kazutoshi
K
Kitahara
Takeshi
T
Imoto
Masaya
M
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001230:Aspergillus / Q000737:chemistry*; D001547:Benzaldehydes / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry; D002465:Cell Movement / Q000187:drug effects*; D003512:Cyclohexanones / Q000737:chemistry* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D018631:ras Proteins / Q000032:analysis / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D001547:Benzaldehydes; D003512:Cyclohexanones; C508258:moverastin A; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; D018631:ras Proteins