Bioprobe Application Research Unit, RIKEN CSRS, Saitama, 351-0198, Japan.
Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan.
Oncol Res. 2023 Jul 21;31(5):655-666. doi: 10.32604/or.2023.030248. eCollection 2023.
Myc belongs to a family of proto-oncogenes that encode transcription factors. The overexpression of c-Myc causes many types of cancers. Recently, we established a system for screening c-Myc inhibitors and identified antimycin A by screening the RIKEN NPDepo chemical library. The specific mechanism of promoting tumor cell metastasis by high c-Myc expression remains to be explained. In this study, we screened approximately 5,600 microbial extracts using this system and identified a broth prepared from sp. RK19-A0402 strongly inhibits c-Myc transcriptional activity. After purification of the hit broth, we identified compounds closely related to the aglycone of cytovaricin and had a structure similar to that of oligomycin A. Similar to oligomycin A, the hit compounds inhibited mitochondrial complex V. The mitochondria dysfunction caused by the compounds induced the production of reactive oxygen species (ROS), and the ROS activated GSK3α/β that phosphorylated c-Myc for ubiquitination. This study provides a successful screening strategy for identifying natural products as potential c-Myc inhibitors as potential anticancer agents.
Myc 属于编码转录因子的原癌基因家族。c-Myc 的过表达会导致多种类型的癌症。最近，我们建立了一种筛选 c-Myc 抑制剂的系统，并通过筛选 RIKEN NPDepo 化学文库鉴定出安密霉素 A。高表达 c-Myc 促进肿瘤细胞转移的具体机制仍有待解释。在这项研究中，我们使用该系统筛选了大约 5600 种微生物提取物，并发现来自 sp. RK19-A0402 的发酵液强烈抑制 c-Myc 的转录活性。在对命中发酵液进行纯化后，我们鉴定出与细胞松弛素糖苷类似的化合物，并具有与寡霉素 A 相似的结构。与寡霉素 A 类似，命中化合物抑制线粒体复合物 V。这些化合物引起的线粒体功能障碍导致活性氧（ROS）的产生，ROS 激活了 GSK3α/β，使 c-Myc 磷酸化进行泛素化。这项研究为鉴定天然产物作为潜在的 c-Myc 抑制剂提供了一种成功的筛选策略，有望成为抗癌药物。
