How Ribosomes Translate Cancer

Abstract

A wealth of novel findings, including congenital ribosomal mutations in ribosomopathies and somatic ribosomal mutations in various cancers, have significantly increased our understanding of the relevance of ribosomes in oncogenesis. Here, we explore the growing list of mechanisms by which the ribosome is involved in carcinogenesis-from the hijacking of ribosomes by oncogenic factors and dysregulated translational control, to the effects of mutations in ribosomal components on cellular metabolism. Of clinical importance, the recent success of RNA polymerase inhibitors highlights the dependence on "onco-ribosomes" as an Achilles' heel of cancer cells and a promising target for further therapeutic intervention.Significance: The recent discovery of somatic mutations in ribosomal proteins in several cancers has strengthened the link between ribosome defects and cancer progression, while also raising the question of which cellular mechanisms such defects exploit. Here, we discuss the emerging molecular mechanisms by which ribosomes support oncogenesis, and how this understanding is driving the design of novel therapeutic strategies. Cancer Discov; 7(10); 1069-87. ©2017 AACR.

Figure 1. RPs implicated in ribosomopathies and/or human cancer

All RPs that have been implicated in ribosomopathies (blue), in cancer (red), or in both (purple) indicated on a structural model of the human ribosome for the small 40S subunit (A) and the large 60S subunit (B). This figure was generated in PyMOL and is based on the human X-ray structure with a resolution of 3 Å (PDM entry 4V6X).

Figure 2. Ribosome dysfunction in cancer

The main differences in the function of ribosomes in cancer cells compared to healthy cells throughout the ribosomal lifecycle are shown. These include upregulation of both ribosome biogenesis and canonical translation initiation by oncogenic factors such as mTOR, c-MYC, and RAS; non-canonical translation initiation at oncogenes such as c-MYC; the use of unconventional start codons; and altered translational fidelity and translational profiles. Current and potential promising therapeutic intervention points at key nodes are indicated.

Figure 3. Oncogenic potential of the extra-ribosomal functions of RPs

(A) Under growth conditions, the cell is actively translating. Ribosome biogenesis is highly efficient and the RPL5-5SRNA-RPL11 complex is rapidly incorporated into mature ribosomes. In this situation, MDM2 is free to bind P53 and promote its degradation. (B) Under stress conditions, translation and ribosome biogenesis decrease, leaving the RPL5-5SRNA-RPL11 complex free to sequester MDM2. P53 is therefore stabilized, suppressing the cell cycle and eventually promoting apoptosis. (C) RPL11 has been shown to negatively regulate cMYC by binding cMYC at the promoter regions of its target genes, thereby inhibiting the recruitment of co activators such as TRAPP. (D) RPL5 and RPL11 have both been shown to associate with cMYC mRNA to promote its degradation through recruitment of the RISC complex which includes Dicer, Argo2 and TRBP.

Figure 4. Model of oncogenesis after initial RP defect

RP defects generally lead to hypoproliferative phenotypes such as anemia presented in ribosomopathies. In this model, the hypoproliferation leads to selective pressure on the cells to acquire secondary mutations. These rescuing mutations could then cause a hyperproliferative phenotype, either singularly or in cooperation with the initial RP defect, leading to clonal expansion of cells with an altered translational profile. This figure is adapted from (95).