Targeting the RNA Polymerase I Transcription for Cancer Therapy Comes of Age

Abstract

Transcription of the ribosomal RNA genes (rDNA) that encode the three largest ribosomal RNAs (rRNA), is mediated by RNA Polymerase I (Pol I) and is a key regulatory step for ribosomal biogenesis. Although it has been reported over a century ago that the number and size of nucleoli, the site of ribosome biogenesis, are increased in cancer cells, the significance of this observation for cancer etiology was not understood. The realization that the increase in rRNA expression has an active role in cancer progression, not only through increased protein synthesis and thus proliferative capacity but also through control of cellular check points and chromatin structure, has opened up new therapeutic avenues for the treatment of cancer through direct targeting of Pol I transcription. In this review, we discuss the rational of targeting Pol I transcription for the treatment of cancer; review the current cancer therapeutics that target Pol I transcription and discuss the development of novel Pol I-specific inhibitors, their therapeutic potential, challenges and future prospects.

Keywords: CX-5461; RNA polymerase I transcription; cancer therapy; ribosome biogenesis.

Figure 1

Schematic overview of ribosome biogenesis. Ribosome biogenesis occurs in nucleoli, which form around actively transcribing repeats of 47S ribosomal DNA. For Pol I transcription to initiate, UBF binds to the regulatory regions and recruits the SL-1 complex that interacts with Pol I via RRN3. Following synthesis, the 47S pre-rRNA is processed and modified to generate the mature 18S, 5.8S, and 28S rRNAs, which together with the 5S rRNA transcribed by Pol III, and ribosomal proteins transcribed by Pol II are assembled to form the 40S and 60S ribosomal subunits. These are subsequently exported from the nucleolus to the cytoplasm, where they form the mature 80S ribosome.

Figure 2

Schematic representation of the nucleolar surveillance pathway. Under normal growth conditions (left), ribosomal proteins (RPs) are assembled with ribosomal RNA into the 40S and 60S subunits in the nucleolus. p53 activity is maintained at low levels by ubiquitin-mediated degradation induced by MDM2. Following nucleolar stress (right), ribosome biogenesis is halted thus RPs, rRNAs, and other nucleolar proteins are released into the nucleoplasm. RPL5 and RPL11 are free to bind to MDM2 and prevent p53 ubiquitylation. p53 is then available for regulation of its target genes leading to cellular responses like cell cycle arrest, senescence, apoptosis and autophagy.

Figure 3

Schematic representation of mechanisms of action of unspecific Pol I transcription inhibitors. Figure showing an overview of the effects of unspecific Pol I transcription inhibitors. Blue - Alkylating agents; Red—Antimetabolites; Green—Plant alkaloids; Purple—Antibiotics. *—DNA adducts (purple), Platinum adducts (blue) or DNA damage (red).

Figure 4

Schematic representation of mechanisms of action of specific Pol I transcription inhibitors. (A) Mode of action of CX-3543, disruption of Nucleolin binding to G4 DNA structures. (B) Mode of action of CX-5461, disruption of Pol I-SL-1 interaction and an unclear role in G4 stabilization. (C) Mode of action of BMH-21, disruption of Pol I complex and ubiquitin-mediated proteasome degradation of POLR1A (RPS194), inhibition of transcription elongation and an unclear role in G4 stabilization.

Figure 5

Schematic representation of the sensitization of MYC-overexpressing cancers to Pol I inhibition therapy. A cell with normal levels of MYC (left) maintains physiological levels of rRNA and RP and therefore produce adequate levels of ribosomes. Overexpression of MYC in cancer cells (right) causes increases of both rRNA and RP allowing for an increased number of ribosomes necessary to maintain uncontrolled growth and proliferation. Therapy with Pol I transcription inhibitors (top) leads to a reduction in rRNA levels while RP levels are maintained at a high level due to the effect of MYC on Pol II transcription. Excess free RP can then activate the NSP, allowing the stabilization of p53 and consequently promotes cell cycle arrest or apoptosis.