Yamauchi Hajime, Matsumaru Takanori, Morita Tomoko, Ishikawa Susumu, Maenaka Katsumi, Takigawa Ichigaku, Semba Kentaro, Kon Shunsuke, Fujita Yasuyuki
Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Sapporo, Japan.
Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Sci Rep. 2015 Oct 20;5:15336. doi: 10.1038/srep15336.
Recent studies have revealed that cell competition can occur between normal and transformed epithelial cells; normal epithelial cells recognize the presence of the neighboring transformed cells and actively eliminate them from epithelial tissues. Here, we have established a brand-new high-throughput screening platform that targets cell competition. By using this platform, we have identified Rebeccamycin as a hit compound that specifically promotes elimination of RasV12-transformed cells from the epithelium, though after longer treatment it shows substantial cytotoxic effect against normal epithelial cells. Among several Rebeccamycin-derivative compounds, we have found that VC1-8 has least cytotoxicity against normal cells but shows the comparable effect on the elimination of transformed cells. This cell competition-promoting activity of VC1-8 is observed both in vitro and ex vivo. These data demonstrate that the cell competition-based screening is a promising tool for the establishment of a novel type of cancer preventive medicine.
最近的研究表明，正常上皮细胞与转化上皮细胞之间会发生细胞竞争；正常上皮细胞能够识别相邻转化细胞的存在，并主动将它们从上皮组织中清除。在此，我们建立了一个全新的针对细胞竞争的高通量筛选平台。通过使用该平台，我们确定了瑞贝卡霉素是一种命中化合物，它能特异性地促进上皮组织中RasV12转化细胞的清除，不过在较长时间处理后，它对正常上皮细胞显示出显著的细胞毒性作用。在几种瑞贝卡霉素衍生物化合物中，我们发现VC1-8对正常细胞的细胞毒性最小，但对转化细胞的清除效果相当。VC1-8的这种促进细胞竞争的活性在体外和体内均有观察到。这些数据表明，基于细胞竞争的筛选是建立新型癌症预防药物的一种有前景的工具。
