Discovery of natural products that modulate cellular responses

2015 Fiscal Year Final Research Report

• Project Area: Chemical Biology using bioactive natural products as specific ligands: identification of molecular targets and regulation of bioactivity
• Project/Area Number: 23102006
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: Keio University
• Principal Investigator: Imoto Masaya 慶應義塾大学, 理工学部, 教授 (60213253)
• Co-Investigator(Renkei-kenkyūsha): KAKEYA HIDEAKI 京都大学, 薬学研究科(研究院), 教授 (00270596) ; TASHIRO ETSU 慶應義塾大学, 理工学部, 専任講師 (00365446)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Keywords: アンドロゲンアンタゴニスト / オートファジー / βカテニン / アンタルライド / キサントフモール / ノナクチン

Outline of Final Research Achievements

In the course of screening for a new AR antagonist, we isolated novel compounds, antarlides A-E, from the Streptomyces sp. BB47. In addition, antarlide B inhibited the transcriptional activity of not only wild type AR but also mutant ARs, which are seen in patients with acquired resistance to clinically used AR antagonists.We next observed that xanthohumol (XN), a prenylated chalcone, modulates autophagy. By using XN-immobilized beads, valosin-containing protein (VCP) was identified as a XN-binding protein. These data indicated that XN inhibited the function of VCP, thereby allowing the impairment of autophagosome maturation. We also screened the compound that induced cell death selectively in tumor cell lines harboring β-catenin mutation from an in-house natural product library, and finally we isolated and found that nonactin. Furthermore, nonactin induced tumor regression only in β-catenin mutated HCT116 xenograft mice.

Free Research Field

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