Ribosome Biogenesis: A Central Player in Cancer Metastasis and Therapeutic Resistance

Abstract

Ribosomes are a complex ensemble of rRNA and ribosomal proteins that function as mRNA translation machines. Ribosome biogenesis is a multistep process that begins in the nucleolus and concludes in the cytoplasm. The process is tightly controlled by multiple checkpoint and surveillance pathways. Perturbations in these checkpoints and pathways can lead to hyperactivation of ribosome biogenesis. Emerging evidence suggests that cancer cells harbor a specialized class of ribosomes (onco-ribosomes) that facilitates the oncogenic translation program, modulates cellular functions, and promotes metabolic rewiring. Mutations in ribosomal proteins, rRNA processing, and ribosome assembly factors result in ribosomopathies that are associated with an increased risk of developing malignancies. Recent studies have linked mutations in ribosomal proteins and aberrant ribosomes with poor prognosis, highlighting ribosome-targeted therapy as a promising approach for treating patients with cancer. Here, we summarize various aspects of dysregulation of ribosome biogenesis and the impact of resultant onco-ribosomes on malignant tumor behavior, therapeutic resistance, and clinical outcome. Ribosome biogenesis is a promising therapeutic target, and understanding the important determinants of this process will allow for improved and perhaps selective therapeutic strategies to target ribosome biosynthesis.

Figure 1.

Ribosome heterogeneity plays a role in tumorigenesis and cancer progression. Ribosome biogenesis begins in the nucleolus where repeats of rDNA reside. RNA Pol I transcription factors, such as UBTF and SL1 bind to active clusters of rDNAs to initiate RNA Pol I transcription and pre-rRNA biosynthesis. Then, pre-rRNA passes through a series of processing and rRNA modifications. Processed rRNA species are combined with ribosomal proteins to generate pre-60S and pre-40s subunits, which are matured and transported to the cytoplasm to participate in protein synthesis. Owing to their uncontrollable proliferation and high demand for ribosomes, cancer cells have upregulated activity of RNA Pol I, leading to increased rRNA biogenesis. In cancer, there are also noncanonical or abnormal rRNA modifications. Ribosomal proteins undergo posttranslational modifications. Differentially modified ribosome proteins can be incorporated in the ribosomes adding to the ribosome heterogeneity. In addition, ribosomal proteins, due to their extraribosomal functions, can contribute to chemo/radioresistance and cancer progression. It is hypothesized that all these alterations and modifications create “onco-ribosomes,” which carry out an aberrant translational program and direct the preferential translation of oncogenes and prosurvival genes that promote cancer progression.