Identification of a chemical inhibitor of the oncogenic transcription factor forkhead box M1
Identification of a chemical inhibitor of the oncogenic transcription factor forkhead box M1
复制标题
DOI：
10.1158/0008-5472.can-06-1576
复制
发表时间：
2006-10-01
期刊：
影响因子：
11.2
通讯作者：
Gartel, Andrei L.
中科院分区：
文献类型：
--
作者：
Radhakrishnan, Senthil K.;Rhat, Uppoor G.;Gartel, Andrei L.
致癌转录因子叉头盒Ml（FoxMl）在许多不同的癌中过表达，而其表达在终末分化细胞中关闭。出于这个原因，FoxMl是癌症治疗中治疗性干预的有吸引力的靶标。作为实现这一目标的第一步，在本研究中，使用高通量的基于细胞的测定系统，我们筛选并分离了抗生素噻唑化合物Siomycin A作为FoxMl的抑制剂。有趣的是，我们观察到Siomycin A能够下调FoxMl的转录活性以及蛋白质和mRNA丰度。因此，我们发现FoxMl的下游靶基因如Cdc25B、Sarvivin和CENPB被抑制。此外，我们观察到与FoxMl抑制的早期报道一致，Siomycin A能够减少软琼脂中细胞的锚定非依赖性生长。此外，我们发现Siomycin A能够选择性地诱导同一来源的转化细胞而不是正常细胞的凋亡。总之，我们的数据表明FoxMl抑制剂Siomycin A可以代表抗癌治疗剂开发的有用起点。
The oncogenic transcription factor forkhead box Ml (FoxMl) is overexpressed in a number of different carcinomas, whereas its expression is turned off in terminally differentiated cells. For this reason, FoxMl is an attractive target for therapeutic intervention in cancer treatment. As a first step toward realizing this goal, in this study, using a high-throughput, cell-based assay system, we screened for and isolated the antibiotic thiazole compound Siomycin A as an inhibitor of FoxMl. Interestingly, we observed that Siomycin A was able to down-regulate the transcriptional activity as well as the protein and mRNA abundance of FoxMl. Consequently, we found that the downstream target genes of FoxMl, such as Cdc25B, Sarvivin, and CENPB, were repressed. Also, we observed that consistent with earlier reports of FoxMl inhibition, Siomycin A was able to reduce anchorage-independent growth of cells in soft agar. Furthermore, we found that Siomycin A was able to induce apoptosis selectively in transformed but not normal cells of the same origin. Taken together, our data suggest that FoxMl inhibitor Siomycin A could represent a useful starting point for the development of anticancer therapeutics.