Induction of Ribosomal Stress by Anticancer Agents

Ribosomes play a crucial role in translational processes, which are composed of more than 80 different ribosomal proteins. In addition to protein translation, the ribosomal proteins also participate in DNA repair, mediating apoptosis, and maintaining cellular homeostasis. Hyperactive ribosomal biogenesis drives a majority of cancers, which offers researchers a great chance to discover cancer therapeutics with less genotoxic that induct ribosomal stress via the p53 tumor suppressor pathway. Creative Biolabs’ experienced team offers professional and comprehensive ribosome-related services for anticancer agent discovery.

Fig.1 The impaired ribosome biogenesis checkpoint (Pelletier, 2018)

How Ribosomal Stress Suppresses Cancer?

The process, by which specific ribosomal proteins attach to the ubiquitin-protein ligase MDM2 (or HDM2 in humans), preventing the p53 ubiquitylation and degradation, is referred to as ribosomal stress or ‘impaired ribosome biogenesis checkpoint (IRBC). The ribosomal proteins or RNA polymerase I (Pol I) inhibitors could induct ribosomal stress and the activation of p53, which could inhibit the proliferation of tumor cells, induct immune-mediated clearance of pre-malignant cells, and activate cellular senescence. To find the cancer treatments, we need to resolve the issues of the natural damage that inducts ribosomal stress and the signals that mediate the response. In recent years, cancer treatments driven by MYC proto-oncogene protein with Pol I inhibitors have been developed. The mechanism of anticancer agents that eliminate tumor cells is that Pol I inhibitors could enhance p53 stabilization through the IRBC complex and thus inhibit ribosome biogenesis.

Anticancer Agents

Pol I inhibitor demonstrates its anticancer effects through the activation of p53 through ribosomal stress and by downregulating the protein synthesis capacity. The first group of Pol I inhibitors includes agents of FDA-approved actinomycin D and acridine derivatives that preferentially intercalate into GC-rich regions of rDNA and prevent the elongation of pre-rRNA chains by Pol I, which also enhance the degradation of DNA-directed RNA polymerase I subunit A1 (RPA1). The second group of Pol inhibitors involves quarfloxin CX-3543 and CX-5461, which attach to G4 DNA and activate DNA damage response (DDR), suppressing rDNA transcription. CX3543 has been well performed in phase I and II clinical trials in patients with solid tumors, or carcinoid and neuroendocrine malignancies, respectively. A phase I/II clinical trial evaluating CX-5461 in BRCA1-deficient and BRCA2-deficient cancers has been initiated as the improvement of the stabilization of G4 by Pol inhibitors also inhibits DNA replication.

Platinum-based drugs are regularly regarded as DNA-damaging agents for cancers. However, oxaliplatin and phenanthriplatin have been proved to inhibit rDNA transcription instead of causing DNA-damaging, which induct p53 or acutely suppress protein synthesis. Oxaliplatin has been indicated as a part of the treatment regimen for stage II or III colorectal cancer (CRC). In addition, the antimetabolites 5-FU and folinic acid also cause damage in Pol I transcription and pre-rRNA processing.

Creative Biolabs provides all aspects of ribosomal technologies, which help researchers and scientists to discover more potential anticancer agents that target ribosome biogenesis.

To get access to our ribosome-related services, please check out the following links:

• Ribosome Separation and Extraction Services
• Ribosome Analysis Services
• Ribosome Marker Antibody Development Services

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References

1. Pelletier, J.; et al. Ribosome biogenesis in cancer: new players and therapeutic avenues. Nature Reviews Cancer. 2018 18(1): 51-63.