Targeting the nucleolus for cancer intervention

Abstract

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.

Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma

“…Free RPL11 and RPL5 are able to bind in an inhibitory manner to the p53 ubiquitin ligase MDM2, resulting in p53 accumulation (16,17,36). However, although CX-5461 treatment robustly increased the binding of critical RPs (RPL11 and RPL5) to MDM2, as expected from previous studies (12), AKTi-1/2 treatment had no effect on RP binding to MDM2 compared with control ( Fig.…”

A Puzzle of Life: Crafting Ribosomal Subunits

“…Further mechanistic and structural insights into ribosome biogenesis may promote the identification and design of small-molecule inhibitors like diazaborine or the ribozinoindoles, which act as specific inhibitors of the AAA-ATPases Drg1 and Rea1, respectively [110,111]. Similar to inhibitors of RNA polymerase I, such molecules are expected to have great potential for the development of novel strategies in cancer treatment [112]. In addition, solving the puzzle of ribosome assembly, by the combination of functional and structural approaches, will be instrumental for future medical advances, including our understanding of ribosomopathies.…”

The R2TP chaperone complex: its involvement in snoRNP assembly and tumorigenesis

“…A common feature of the cancer cells is abnormally enlarged nucleolus, as a result of hyperactive ribosome biogenesis (41). Consequently, cellular processes that are related to ribosome biogenesis, such as the biosynthesis of ribosomal proteins, rRNA, snoRNAs and core proteins of snoRNPs, are expected to be highly activated (41)(42)(43)(44).…”

“…Consequently, cellular processes that are related to ribosome biogenesis, such as the biosynthesis of ribosomal proteins, rRNA, snoRNAs and core proteins of snoRNPs, are expected to be highly activated (41)(42)(43)(44). In support of this argument, the deregulation of snoRNA/ snoRNP biogenesis has been reported in various cancer cell types [reviewed in (45)].…”