Ribosome-an Aussichtsreich Target for Cancer Therapy

Introduction to Ribosome and Its Functions

Being an important organelle widely present in the eukaryotic nucleus, the ribosome is a ribonucleoprotein complex composed of two subunits of different sizes (40S and 60S). The 40S subunit is consist of 18S rRNA and 33 proteins while the 60S subunit is composed of three different rRNAs, 5S, 5.8S, and 28S, as well as 49 ribosomal proteins. Both subunits are essential for protein synthesis. The decoding center (DC) of the small subunit controls the initiation of the translation process, while the peptidyl transferase center (PTC) of the large subunit can catalyze the chemical bonding between different amino acids. Moreover, compared with other lower eukaryotes, the human ribosome is more complex and contains some extra expansion regions, which also play a role in translation.

Ribosome Biogenesis Process

The synthesis of ribosomes is a sophisticated process involving hundreds of genes in eukaryotic cells. In detail, the whole process can be divided into four main steps:

1. Transcription and processing of precursor ribosomal nucleic acid(pre-rRNAs)
2. Synthesis of ribosomal protein
3. Integration and assembly of ribosomal protein and pre-rRNAs
4. Nuclear export of ribosomal particles

As shown in figure 1, different functional factors are required to coordinate at different stages, which can modify and cleave pre-rRNA and help assemble and export ribosomal particles.

Fig.1 Schematic illustration of the mechanism of ribosome biogenesis in eukaryotes. (Greber BJ, 2016)

Relationship Between Ribosome Biogenesis and Cancer Pathogenesis

Compared with normal cells, cancer cells express a much larger number of proteins, and protein synthesis requires more ribosomes, so the increased trend of ribosome biogenesis in cancer cells is significant. It also has been found that the mutation of several ribosomal proteins can result in cancer. In addition, recent studies have found a close relationship between inflammatory processes and ribosome biogenesis. IL-6 can stimulate the transcription of rRNA by a c-Myc-dependent pathway and this rRNA would assemble with ribosomal proteins to form new functional ribosomes. In conclusion, the maintenance of the physiological activity of cancer cells is closely related to ribosome biosynthesis. Therefore, ribosomes can be used as an ideal anticancer target for drug development.

Ribosome as a Target in Cancer Diseases

Myasnikov's study (2016) has proved that the specificity of different eukaryote-specific antibiotics towards cytosolic is the ribosome. Furthermore, the deletion of the ribosomal protein eS6 (S6RP) gene leads to the inhibition of cancer cells, which further confirms that ribosomes are potential anticancer targets. Hence, as shown in Table 1, several drugs targeting ribosomes and inhibiting protein synthesis have been approved by the FDA for the treatment of tumors.

Table.1 Effect of different drugs on inhibition of ribosome biogenesis in cancer cells. (Temaj, 2022)

Conclusion

Ribosome biogenesis and the synthesis of proteins controlled by ribosomes play an important role in the germinal and metastasis of tumors. RNAs and proteins involved in the ribosome biogenesis pathway can be used as effective targets for anticancer drugs.

References

1. Greber, B.J. Mechanistic insight into eukaryotic 60S ribosomal subunit biogenesis by cryo-electron microscopy. RNA. 2016 Nov;22(11):1643-1662.
2. Temaj G., et al. Ribosome-Directed Therapies in Cancer. Biomedicines. 2022; 10(9):2088.

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