Protein synthesis control in cancer: selectivity and therapeutic targeting

Abstract

Translational control of mRNAs is a point of convergence for many oncogenic signals through which cancer cells tune protein expression in tumorigenesis. Cancer cells rely on translational control to appropriately adapt to limited resources while maintaining cell growth and survival, which creates a selective therapeutic window compared to non-transformed cells. In this review, we first discuss how cancer cells modulate the translational machinery to rapidly and selectively synthesize proteins in response to internal oncogenic demands and external factors in the tumor microenvironment. We highlight the clinical potential of compounds that target different translation factors as anti-cancer therapies. Next, we detail how RNA sequence and structural elements interface with the translational machinery and RNA-binding proteins to coordinate the translation of specific pro-survival and pro-growth programs. Finally, we provide an overview of the current and emerging technologies that can be used to illuminate the mechanisms of selective translational control in cancer cells as well as within the microenvironment.

Keywords: cancer; protein synthesis; translation and protein quality; translation inhibitors; translational control.

Figure 1. Oncogenic regulation and therapeutic targeting of the eIF4F complex

(A) In various cancer types, oncogenic pathways regulate the expression and activity of the translation machinery, converging on the eIF4F complex. The Myc oncogene promotes transcription of eIF4E, eIF4A, and several ribosomal proteins. MAPK‐interacting serine/threonine kinase MNK1, activated downstream of the RAS/ERK pathway, phosphorylates eIF4E which is crucial for the activity of the protein. In addition, mTORC1, which acts downstream of PI3K/AKT, phosphorylates 4E‐binding proteins, 4EBPs, which in turn release eIF4E to promote translation. Unphosphorylated 4EBPs compete with eIF4G to bind to eIF4E and inhibit translation. (B) Compounds targeting eIF4F complex inhibit cancer cell proliferation and tumorigenesis in vitro and in vivo. Tomivosertib (eFT508) inhibits MNK1, which regulates the activity of eIF4E through phosphorylation, and is showing promising results in clinical trials. 4EGI‐1, 4E1RCat, and 4E2RCat target the eIF4E‐eIF4G interaction to block cap‐dependent translation. Rocaglate derivatives, Zotatifin (eFT226), Rocaglamide (RocA), Silvestrol, and CR‐1‐31‐B, inhibit the activity of eIF4A by clamping the protein to polypurine stretches of the RNA. Among them, Zotatifin is already in Phase II clinical trials.

Figure 2. Roles of eIF3 and eIF5A in selective translational control

(A) The eIF3 complex with 13 subunits regulates specialized translation of mRNAs encoding proteins involved in differentiation, electron transport chain (ETC), cell cycle, apoptosis, and metabolic reprogramming. Different mechanisms of eIF3‐dependent translation are shown. eIF3 can directly bind to the cap via its 3D subunit and drive cap‐independent translation (JUN mRNA). eIF3 can recruit the ribosome to m⁶A modification containing mRNA for translation of specific mRNAs (HSP70 mRNA). In addition, METTL3 can recruit eIF3 to transcripts containing m⁶A modification in their 5′UTR and promote translation (TAZ mRNA). (B) eIF5A plays a role as ribosomal pause relief factor. eIF5A promotes peptide bond formation when the ribosome is stalled on a polyproline stretch. The unique post‐translational modification in eIF5A, hypusination, is required for the activity of the protein.

Figure 3. Codon usage and tRNAs in cancer

Cancer‐specific repertoire of tRNAs, the decoding components of the translation machinery, promote selective translation to maintain cancer cell fitness. RNA polymerase III, which is regulated by three major oncogenic pathways, MAPK/ERK, MYC, and PI3K/mTOR, can specifically alter the abundance and availability of specific tRNAs in cancer cells to promote translation elongation efficiency for specific subsets of mRNAs based on their codon composition. As an example, breast cancer cells express high levels of tRNA^Glu _UUC and tRNA^Arg _CCG which enhance translation of EXOSC2 and GRIPAP1 mRNAs in a codon‐specific manner to promote tumorigenesis.

Figure 4. RNA sequence elements regulate selective translation

(A) RNA sequence cis‐regulatory elements in both the 5′UTR and 3′UTR of mRNAs play a role in specifying transcripts for translation downstream of certain oncogenic signals. For example, both the TOP and PRTE motifs mediate the translation of transcripts sensitive to mTOR activity. These RNA sequence elements function as part of a coordinated mechanism to regulate the translation of specific pro‐oncogenic programs, such as EMT (GRE), metabolic dysregulation (PRTE), and response to oxidative stress (CERT). Consensus sequences of each motif are shown. (B) RNA sequence elements interface with RNA‐binding proteins (RBPs) to regulate the translation of specific transcripts. A well‐studied example is the RBP LARP1’s modulation of the translation of 5′TOP motif containing transcripts. When mTORC1 is inactive, LARP1 binds the TOP motif to block eIF4F binding to the mRNA cap. However, active mTORC1 phosphorylates and physically binds LARP1 to allow eIF4F to access the cap and promote translation initiation. (C) RNA sequence features in the 5′UTR can alter translation of the main ORF (mORF). Under homeostatic conditions, the translation machinery engages upstream ORFs (uORFs) to diminish mORF translation. However, under oncogenic stress, uORF translation is suppressed to promote the translation of the mORF, which often encodes oncogenes or pro‐survival factors. In a similar way, cancer cell signaling can promote translation initiation at alternative start codons that are in‐frame with the main ORF to generate N‐terminally extended proteins. These alternative proteoforms possess different functions from the canonical protein as has been well described for the tumor suppressor PTEN.

Figure 5. RNA structures mediate translational control

(A) The 5′UTRs of key pro‐tumorigenic transcripts contain RNA structures that promote selective translation initiation. The internal ribosome entry site (IRES) allows for cap‐independent translation of mRNAs critical to cancer cell growth and survival in the setting of decreased cap‐dependent translation, such as under low nutrient conditions or hypoxia. A key example of IRES‐dependent translational control is the oncogene MYC. The coordinated binding of the RBPs YBX1 and PTBP1 and the translation initiation machinery to the IRES‐like structure in the MYC 5′UTR can initiate cap‐independent translation in a cancer setting. Another example is the anti‐apoptotic factor XIAP. Binding of eIF3 to the cellular IRES located in the XIAP 5'UTR drives cap‐independent translation. (B) Structures in the 3′UTR of mRNAs can regulate translational elongation to coordinate the selective expression of key hallmarks of cancer. One important example is the function of the TGFβ‐activated translational (BAT) element in mediating the synthesis of proteins involved in EMT processes.