Exploiting Translation Machinery for Cancer Therapy: Translation Factors as Promising Targets

Abstract

Eukaryotic protein translation has slowly gained the scientific community's attention for its advanced and powerful therapeutic potential. However, recent technical developments in studying ribosomes and global translation have revolutionized our understanding of this complex multistep process. These developments have improved and deepened the current knowledge of mRNA translation, sparking excitement and new possibilities in this field. Translation factors are crucial for maintaining protein synthesis homeostasis. Since actively proliferating cancer cells depend on protein synthesis, dysregulated protein translation is central to tumorigenesis. Translation factors and their abnormal expressions directly affect multiple oncogenes and tumor suppressors. Recently, small molecules have been used to target translation factors, resulting in translation inhibition in a gene-specific manner, opening the door for developing translation inhibitors that can lead to novel chemotherapeutic drugs for treating multiple cancer types caused by dysregulated translation machinery. This review comprehensively summarizes the involvement of translation factors in tumor progression and oncogenesis. Also, it sheds light on the evolution of translation factors as novel drug targets for developing future therapeutic drugs for treating cancer.

Keywords: cancer therapeutics; drug target; eIF1; eIF4F; small-molecule inhibitors; translation initiation.

Figure 1

Schematic representation of eukaryotic translation initiation. Translation initiation is a multi-step process. In step 1, the ternary complex (TC) is formed wherein eIF2 (α, β, and γ), initiator methionyl tRNA (Met-tRNAMeti), and GTP assemble. In step 2, 40S ribosomal subunit, ternary complex, eIF1, eIF1A, eIF3, and eIF5 assembles to form 43S pre-initiation complex PIC). Simultaneously, the eIF4F complex consisting of eIF4E, eIF4A and eIF4G, binds to 5’cap-mRNA (step 3). Next, the 43S PIC is recruited onto the mRNA (step 4). eIF4A helps release mRNA secondary structure in 5’UTR and help facilitate pre-initiation 43S complex scanning of 5’UTR in 5’ to 3’ direction. Upon the AUG start codon recognition, all the translation factors (i.e., eIFs) are released that follows the joining of a 60S large subunit, leading to the formation of elongation-competent 80S ribosome marking the end of the translation initiation stage of translation.

Figure 2

Schematic representation of eukaryotic translation elongation followed by termination. Translation elongation marks the peptidyl transfer reaction happening in the core of the ribosome. eEF1A brings amino-acyl-tRNA to the A-site of the 80S ribosome. eEF1A is released following GTP hydrolysis. In the next step, a peptidyl transfer reaction occurs by eEF2, wherein nucleophilic tRNA on the A site attacks the electrophilic peptidyl-tRNA in the P-site. Upon reaching the stop codon, eukaryotic release factors (RFs) bind to the A-site and allow the release of the completed polypeptide chain, marking the termination of the translation process.

Figure 3

Collection of selected translation inhibitors targeting different translation factors. (A) eIF4A inhibitors: silvestrol and other synthetic Rocaglamide analog CR-1-31-B, Zotatiffin, and marine compound eIF4A inhibitor Pateamine A. (B) eIF4E inhibitors: ribavirin, 4EG1-I, 4E1Rcat, and 4E2RCat. (C) eEF1A inhibitors: didemnin A, plitidepsin, narciclasine, and nannocyctin.

Figure 4

Potential direct inhibitors of translation factors are being explored for developing novel cancer therapeutics. Essential and potential drug target translation factors in the translation machinery and the compounds that target them are shown. Red bar-headed lines indicate inhibition. As shown, almost every translation factor in translation initiation can be targeted by small-molecule inhibitors, including eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and ternary complex formation (upper left), eIF4E and eIF4F complex formation, enzymatic activity and cap-binding (upper right), eIF4A (center), eIF4G1 (center right), eIF3 (upper middle) as well as first peptide bond formation or initiating ribosome (center left) and translation elongation by eEF1A (bottom left).