Ribosome-Directed Therapies in Cancer

Abstract

The human ribosomes are the cellular machines that participate in protein synthesis, which is deeply affected during cancer transformation by different oncoproteins and is shown to provide cancer cell proliferation and therefore biomass. Cancer diseases are associated with an increase in ribosome biogenesis and mutation of ribosomal proteins. The ribosome represents an attractive anti-cancer therapy target and several strategies are used to identify specific drugs. Here we review the role of different drugs that may decrease ribosome biogenesis and cancer cell proliferation.

Keywords: cancer; rRNA and tRNA inhibition; ribosome; target drugs.

Figure 1

Eukaryotic mRNA undergoes several steps of processing in the nucleolus, such as 7-methylguanosine (m7G) at the 5′ and poly A-tail in the 3′-end. Ribosomes are recruited by mRNA through coordinated multiple processes. Two protein complexes, eukaryote translation initiation factor (eIF4F), which comprises eIF4E (cap-binding protein), eIF4G (scaffold protein), and eIF4A (RNA helicase), and the ternary complex, which includes eIF2-GTP and initiation tRNA (Met-tRNAiMet), have pivotal roles in translation initiation. The mRNA circularization occurs in the interaction of eIF4G with poly A-tail binding protein (PABP). The eIF4F complex displays a secondary structure in the 5′ untranslated region (5′UTR) of mRNA. The mTOR complex 1 controls the initiation of translation through the ternary complex and eIF4F complex. Moreover, the interaction of eIF4B with eIF4A increases the helicase activity of the latter.

Figure 2

Inhibition of eukaryotic rRNA processing in different steps. The rRNA processing scheme presented here from 35S pre-rRNA to the mature rRNA (18S, 5.8S, and 25S) is complemented with different inhibitors and their potentially targeted ribosomal maturation.

Figure 3

Overview of protein synthesis in bacteria and inhibition by different antibiotics. First step: initiation of protein synthesis assisted by initiation factors (IF1, 2, 3), location of the start codon in mRNA, and connection of the initiation tRNA in the peptidyl (P) site. During translation elongation, EF-Tu-delivered aminoacyl-tRNA are selected and then accommodated in the aminoacyl tRNA. The antibiotic (green highlighted)- and macrolide-inhibition of peptide bond formation depends on the structure of the nascent protein. During translocation, the A site-bound peptidyl-tRNA moves into the P site, and the tRNA with a free 3′ end is relocated into the exit E site. When the ribosome encounters a stop codon, it enters the termination phase. During this phase, the completed protein is released with the help of termination factors (RF1 or RF2 and RF3). The last step is the recycling phase, when the combination of ribosome recycling factor (RRF) and EF-G splits the ribosome into its subunits.