Targeting the nucleolus for cancer intervention

• Published in: Biochimica et biophysica acta 2014-06, Vol.1842 (6), p.802-816
• Main Authors: Quin, Jaclyn E., Devlin, Jennifer R., Cameron, Donald, Hannan, Kate M., Pearson, Richard B., Hannan, Ross D.
• Format: Article
• Language: English
• Subjects: Benzothiazoles - pharmacology; Cancer; Cell Nucleolus - genetics; Cell Transformation, Neoplastic - genetics; CX-5461; DNA, Ribosomal - genetics; DNA, Ribosomal - metabolism; Genes, myc - genetics; Humans; MYC; Naphthyridines - pharmacology; Neoplasms - genetics; Neoplasms - pathology; Nucleolar stress; p53; Ribosome biogenesis; Ribosomes - genetics; Ribosomes - metabolism; RNA Polymerase I - antagonists & inhibitors; RNA Polymerase I - genetics; RNA Polymerase I - metabolism; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2013.12.009

The contribution of the nucleolus to cancer is well established with respect to its traditional role in facilitating ribosome biogenesis and proliferative capacity. More contemporary studies however, infer that nucleoli contribute a much broader role in malignant transformation. Specifically, extra-ribosomal functions of the nucleolus position it as a central integrator of cellular proliferation and stress signaling, and are emerging as important mechanisms for modulating how oncogenes and tumor suppressors operate in normal and malignant cells. The dependence of certain tumor cells to co-opt nucleolar processes to maintain their cancer phenotypes has now clearly been demonstrated by the application of small molecule inhibitors of RNA Polymerase I to block ribosomal DNA transcription and disrupt nucleolar function (Bywater et al., 2012 [1]). These drugs, which selectively kill tumor cells in vivo while sparing normal cells, have now progressed to clinical trials. It is likely that we have only just begun to scratch the surface of the potential of the nucleolus as a new target for cancer therapy, with “suppression of nucleolar stress” representing an emerging “hallmark” of cancer. This article is part of a Special Issue entitled: Role of the Nucleolus in Human Disease. •Ribosome biogenesis is consistently hyperactivated in cancer.•Pol I transcription of rRNA genes is regulated by tumor suppressors and oncogenes.•The nucleolus performs extra-ribosomal functions that may contribute to cancer.•Inhibiting Pol I transcription of rRNA genes can activate p53 in cancer cells.•Targeting Pol I transcription of rRNA genes can effectively treat cancer.