Woods Simone J, Hannan Katherine M, Pearson Richard B, Hannan Ross D
Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
Division of Research, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3052, Australia.
Biochim Biophys Acta. 2015 Jul;1849(7):821-9. doi: 10.1016/j.bbagrm.2014.10.007. Epub 2014 Nov 11.
Recent studies have highlighted the fundamental role that key oncogenes such as MYC, RAS and PI3K occupy in driving RNA Polymerase I transcription in the nucleolus. In addition to maintaining essential levels of protein synthesis, hyperactivated ribosome biogenesis and nucleolar function plays a central role in suppressing p53 activation in response to oncogenic stress. Consequently, disruption of ribosome biogenesis by agents such as the small molecule inhibitor of RNA Polymerase I transcription, CX-5461, has shown unexpected, potent, and selective effects in killing tumour cells via disruption of nucleolar function leading to activation of p53, independent of DNA damage.
This review will explore the mechanism of DNA damage-independent activation of p53 via the nucleolar surveillance pathway and how this can be utilised to design novel cancer therapies.
Non-genotoxic targeting of nucleolar function may provide a new paradigm for treatment of a broad range of oncogene-driven malignancies with improved therapeutic windows. This article is part of a Special Issue entitled: Translation and Cancer.
最近的研究突出了关键癌基因如MYC、RAS和PI3K在驱动核仁中RNA聚合酶I转录方面的基本作用。除了维持蛋白质合成的必要水平外，过度激活的核糖体生物合成和核仁功能在响应致癌应激时抑制p53激活方面起着核心作用。因此，诸如RNA聚合酶I转录的小分子抑制剂CX-5461等药物破坏核糖体生物合成，已显示出通过破坏核仁功能导致p53激活来杀死肿瘤细胞的意外、强效和选择性作用，这与DNA损伤无关。
本综述将探讨通过核仁监测途径非依赖DNA损伤激活p53的机制，以及如何利用这一机制设计新的癌症治疗方法。
对核仁功能的非基因毒性靶向可能为治疗多种致癌基因驱动的恶性肿瘤提供一种新的范例，并改善治疗窗口。本文是名为“翻译与癌症”的特刊的一部分。
