Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward

Abstract

Rapid growth and unrestrained proliferation is a hallmark of many cancers. To accomplish this, cancer cells re-wire and increase their biosynthetic and metabolic activities, including ribosome biogenesis (RiBi), a complex, highly energy-consuming process. Several chemotherapeutic agents used in the clinic impair this process by interfering with the transcription of ribosomal RNA (rRNA) in the nucleolus through the blockade of RNA polymerase I or by limiting the nucleotide building blocks of RNA, thereby ultimately preventing the synthesis of new ribosomes. Perturbations in RiBi activate nucleolar stress response pathways, including those controlled by p53. While compounds such as actinomycin D and oxaliplatin effectively disrupt RiBi, there is an ongoing effort to improve the specificity further and find new potent RiBi-targeting compounds with improved pharmacological characteristics. A few recently identified inhibitors have also become popular as research tools, facilitating our advances in understanding RiBi. Here we provide a comprehensive overview of the various compounds targeting RiBi, their mechanism of action, and potential use in cancer therapy. We discuss screening strategies, drug repurposing, and common problems with compound specificity and mechanisms of action. Finally, emerging paths to discovery and avenues for the development of potential biomarkers predictive of therapeutic outcomes across cancer subtypes are also presented.

Keywords: RNA polymerase I; cancer; nucleolus; p53; ribosome biogenesis; translation.

Figure 1

Cellular targets and processes for small molecules that directly, or indirectly, can interfere with ribosome biogenesis. Figure was created with Biorender.com under academic license.

Figure 2

A schematic timeline of the most common substructures found in RiBi inhibitory cancer drugs. Drugs known to interact with the RiBi machinery are listed along with their name, trade name, and clinical approval year. Investigational drugs are shown with their name and the year they first appeared in the literature in italics with an asterisk. The drugs are grouped based on their substructure, shown on the green-colored box, with the initial discovery or synthesis year. The figure was created with Biorender.com under academic license.

Figure 3

Examples of how ActD and BMH-21 affects nucleolar markers. (A) EGFP-NPM1 intracellular re-distribution upon treatment with a low concentration of ActD (5nM). On the left control, live unfixed U2OS cells; on the right, U2OS cells treated with ActD. The solvent for ActD in this experiment was ethanol. Note the more intense nucleoplasmic signal, while the round nucleolar areas have shrunken in the ActD-treated sample. Image by M. Lindström. (B) Nucleolar disruption induced by BMH-21 in U2OS cells. AgNOR staining of U2OS cells treated with DMSO (left) or 1 μM of BMH-21 (right) for six hours. Zoom-in of select cells in the lower row. Scale bar 10 μm. Image by A. Zisi.