Molecular Cancer Biology Program and Centre for Drug Research, University of Helsinki, Helsinki 00014, Finland.
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Cancer Cell. 2014 Jan 13;25(1):77-90. doi: 10.1016/j.ccr.2013.12.009.
We define the activity and mechanisms of action of a small molecule lead compound for cancer targeting. We show that the compound, BMH-21, has wide and potent antitumorigenic activity across NCI60 cancer cell lines and represses tumor growth in vivo. BMH-21 binds GC-rich sequences, which are present at a high frequency in ribosomal DNA genes, and potently and rapidly represses RNA polymerase I (Pol I) transcription. Strikingly, we find that BMH-21 causes proteasome-dependent destruction of RPA194, the large catalytic subunit protein of Pol I holocomplex, and this correlates with cancer cell killing. Our results show that Pol I activity is under proteasome-mediated control, which reveals an unexpected therapeutic opportunity.
我们定义了一种用于癌症靶向的小分子先导化合物的活性和作用机制。我们表明，该化合物 BMH-21 在 NCI60 癌细胞系中具有广泛而有效的抗肿瘤活性，并在体内抑制肿瘤生长。BMH-21 结合富含 GC 的序列，这些序列在核糖体 DNA 基因中高频出现，并强烈且快速地抑制 RNA 聚合酶 I（Pol I）转录。引人注目的是，我们发现 BMH-21 导致蛋白酶体依赖性破坏 RPA194，即 Pol I 全酶复合物的大亚基蛋白，这与癌细胞杀伤相关。我们的结果表明，Pol I 活性受到蛋白酶体介导的控制，这揭示了一个意外的治疗机会。
