Dysregulation of mRNA translation and energy metabolism in cancer

Abstract

Dysregulated mRNA translation and aberrant energy metabolism are frequent in cancer. Considering that mRNA translation is an energy demanding process, cancer cells must produce sufficient ATP to meet energy demand of hyperactive translational machinery. In recent years, the mammalian/mechanistic target of rapamycin (mTOR) emerged as a central regulatory node which coordinates energy consumption by the translation apparatus and ATP production in mitochondria. Aberrant mTOR signaling underpins the vast majority of cancers whereby increased mTOR activity is thought to be a major determinant of both malignant translatomes and metabolomes. Nonetheless, the role of mTOR and other related signaling nodes (e.g. AMPK) in orchestrating protein synthesis and cancer energetics is only recently being unraveled. In this review, we discuss recent findings that provide insights into the molecular underpinnings of coordination of translational and metabolic programs of cancer cells, and potential strategies to translate these findings into clinical treatments.

Keywords: Cancer; Energy metabolism; mRNA translation; mTOR.

Figure 1. Energy consumption by the eukaryotic translational machinery

In eukaryotes, protein synthesis occurs in four major steps: initiation, elongation, termination and ribosome recycling. (A) Step 1: Initiation. Initiation requires the assembly of the 43S pre-initiation complex (PIC) and eIF4F (1). The 5′ capped mRNA is activated in an ATP-dependent manner by eIF4F. The 48S PIC is assembled by association of 43S PIC and the eIF4F complexes (2). As a part of eIF4F, eIF4A unwinds 5′UTR in an ATP-dependent manner while the 5′UTR is scanned in the 5′-->3′ direction (3). Recognition of the translation initiation codon triggers hydrolysis of GTP from the ternary complex (TC) resulting in TC release (4). This is followed by the dissociation of other initiation factors (eIFs). eIF5B accelerates the release of eIFs and the joining of the 60S ribosomal subunit which is accompanied by the hydrolysis of an additional GTP (4). (B) Step 2: Elongation. Aminoacyl-tRNAs (aa-tRNA) are recruited by elongation factor (eEF) 1A. The anticodon of the incoming aa-tRNA is matched against the mRNA codon positioned in the A site resulting in the hydrolysis of GTP which is stimulated by eIF1B leading to the release of eEF1A (1). The growing polypeptide chain is covalently linked to the new amino acid, leaving an empty tRNA in the P site (2). As the mRNA moves one codon forward, the empty tRNA from the P site is displaced to the E site as the peptidyl tRNA is translocated into the P site which is facilitated by eEF2 and requires GTP hydrolysis. tRNAs are aminoacylated by aminoacyl tRNA synthetase, which requires hydrolysis of ATP to AMP (3). These steps are repeated until the ribosome encounters an in-frame stop codon. (C) Step 3: Termination. An in-frame stop codon is positioned in the A site (1). Release factors (eRFs) 1, 2 and 3 assemble with GTP forming a complex near the A site (1). Upon recognition of the stop codon by eRF1 and eRF2, GTP hydrolysis is triggered by eRF3 resulting in the release of the polypeptide chain (2). eRFs are released followed by the dissociation of the 40S, 60S ribosomal subunits and mRNA (3). The ribosomal subunits are then recycled. Abbreviations: eIF, eukaryotic initiation factor, eRF, eukaryotic release factor, eEF, eukaryotic elongation factor, PIC, preinitiation complex, TC, ternary complex, PABP, poly(A) binding protein, tRNA_i^Met, initiator tRNA, M7G, 7-methylguanylate cap.

Figure 2. Simplified scheme of signaling pathways that coordinate energy production and protein synthesis

The mammalian/mechanistic target of rapamycin (mTOR) pathway emerged as a pivotal regulator of protein synthesis and energy metabolism. It is present in at least two functionally and structurally distinct complexes mTORC1 and mTORC2. mTORC1 integrates a number of signals via various upstream pathways. For instance, hormones and growth factors (e.g. insulin and IGFs) which activate receptor tyrosine kinases (e.g. insulin receptor) lead to activation of PI3K which via AKT inactivates TSC1/2 complex. TSC1/2 complex acts as a GAP (GTPase-activating protein) towards the Ras homologue enriched in brain (RHEB) GTPase, which converts RHEB-GTP to its inactive RHEB-GDP form thus preventing activation of mTORC1. In addition, nutrients and in particular amino acids activate mTORC1 via RAG GTPases, while the effects of oxygen tension and energy status in the cell on mTORC1 activity are mediated by REDD1 and AMPK, respectively. mTORC1 stimulates translation by modulating the activity of its downstream effectors including S6Ks, 4EBPs and eEF2K. mTOR simultaneously perturbs other metabolic processes including induction of lipogenesis and glycolysis, and suppression of autophagy. Increase in energy consumption under conditions wherein mTOR is activated is compensated by the perturbations in the translatome that allow selective increase in translation of the nuclear-encoded mRNAs that encode proteins that bolster mitochondrial number and functions. In addition to mTOR, a number of stress conditions including amino acid deprivation, ER stress, heme deficiency and viral infection translation is downregulated via eIF2α kinases which phosphorylate eIF2α and impedes the recycling of ternary complex. Emerging results suggest that the activity of AMPK, mTOR and/or eIF2α phosphorylation may be co-regulated. Abbreviations: PDK1, 3-phosphoinositide-dependent protein kinase-1, RAG, Ras-related GTP-binding protein, RPS6, ribosomal protein S6, PIP3, Phosphatidylinositol (3,4,5)-trisphosphate, PIP2, Phosphatidylinositol 4,5-bisphosphate, eIF, eukaryotic initiation factor, eEF, eukaryotic elongation factor.