小分子在癌细胞中选择性地抑制 MYC 转录。
Small molecule selectively suppresses MYC transcription in cancer cells.
机构信息
California Institute for Biomedical Research, La Jolla, CA 92037.
California Institute for Biomedical Research, La Jolla, CA 92037
出版信息
Proc Natl Acad Sci U S A. 2017 Mar 28;114(13):3497-3502. doi: 10.1073/pnas.1702663114. Epub 2017 Mar 14.
Abstract
Stauprimide is a staurosporine analog that promotes embryonic stem cell (ESC) differentiation by inhibiting nuclear localization of the MYC transcription factor NME2, which in turn results in down-regulation of MYC transcription. Given the critical role the oncogene MYC plays in tumor initiation and maintenance, we explored the potential of stauprimide as an anticancer agent. Here we report that stauprimide suppresses MYC transcription in cancer cell lines derived from distinct tissues. Using renal cancer cells, we confirmed that stauprimide inhibits NME2 nuclear localization. Gene expression analysis also confirmed the selective down-regulation of MYC target genes by stauprimide. Consistent with this activity, administration of stauprimide inhibited tumor growth in rodent xenograft models. Our study provides a unique strategy for selectively targeting MYC transcription by pharmacological means as a potential treatment for MYC-dependent tumors.
摘要
Stauprimide 是一种 Staurosporine 类似物，通过抑制 MYC 转录因子 NME2 的核定位，促进胚胎干细胞 (ESC) 分化，从而导致 MYC 转录下调。鉴于致癌基因 MYC 在肿瘤起始和维持中发挥关键作用，我们探讨了 stauprimide 作为抗癌药物的潜力。在这里，我们报告 stauprimide 抑制了源自不同组织的癌细胞系中的 MYC 转录。使用肾癌细胞，我们证实 stauprimide 抑制了 NME2 的核定位。基因表达分析也证实了 stauprimide 对 MYC 靶基因的选择性下调。与这种活性一致，stauprimide 的给药抑制了啮齿动物异种移植模型中的肿瘤生长。我们的研究为通过药理学手段选择性靶向 MYC 转录提供了一种独特的策略，作为治疗依赖 MYC 的肿瘤的潜在方法。
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