Eukaryotic translation initiation factors as promising targets in cancer therapy

Abstract

The regulation of the translation of messenger RNA (mRNA) in eukaryotic cells is critical for gene expression, and occurs principally at the initiation phase which is mainly regulated by eukaryotic initiation factors (eIFs). eIFs are fundamental for the translation of mRNA and as such act as the primary targets of several signaling pathways to regulate gene expression. Mis-regulated mRNA expression is a common feature of tumorigenesis and the abnormal activity of eIF complexes triggered by upstream signaling pathways is detected in many tumors, leading to the selective translation of mRNA encoding proteins involved in tumorigenesis, metastasis, or resistance to anti-cancer drugs, and making eIFs a promising therapeutic target for various types of cancers. Here, we briefly outline our current understanding of the biology of eIFs, mainly focusing on the effects of several signaling pathways upon their functions and discuss their contributions to the initiation and progression of tumor growth. An overview of the progress in developing agents targeting the components of translation machinery for cancer treatment is also provided. Video abstract.

Keywords: Cancer; MAPK; PI3K/Akt; eIF; mRNA translation; mTOR.

Fig. 1

Schematic representation of the pathway of eukaryotic translation initiation. The whole process of eukaryotic translation initiation can be divided into nine stages: a the recycling of separated ribosomal subunits and eIFs which are generated from the previous mRNA translations. b the formation of eIF2-GTP-Met-tRNAi^Met ternary complex. c the formation of 43S PIC which is composed of eIF2-GTP-Met-tRNAi^Met ternary complex, 40S ribosomal subunits, eIF1, eIF1A, eIF3 and eIF5. d the activation of mRNA by eIF4F complex with the assistance of eIF4B, eIF3 and PABP. e the attachment of 43S PIC to mRNA. f the scanning of mRNA 5’UTR in a 5’-3’ direction by 43S PIC. g the recognition of start codon and the formation of 48S initiation complex. h the jointing of 60S ribosomal subunits to the 48S complex with the assistance of eIF5B-GTP and eIF1A, and the concomitant displacement of eIF2-GDP and other factors including eIF1, eIF3, eIF4B, eIF4F and eIF5. i hydrolysis of eIF5B-bound GTP and release of eIF1A and eIF5B-GDP from the 80S ribosome, mRNA translation enters the elongation stage

Fig. 2

The major substrates of mTORC1 and their signaling to the translational machinery. 4E-BPs and S6Ks are the two major mediators of the effects of mTORC1 on mRNA translation. In non-phosphorylated states, 4E-BPs block the assembly of the eIF4F complex by competing with eIF4G for binding to eIF4E. When phosphorylated by mTORC1, the hyper-phosphorylation of 4E-BPs facilitates their dissociation from eIF4E, allowing the interaction of eIF4E and eIF4G and the assembly of eIF4F complex. In addition to 4E-BPs, S6Ks also mediate the effects of mTORC1 on mRNA translation. The major S6Ks substrates involved in the regulation of translation are rpS6, eIF4B, eEF2K and PDCD4, which are also phosphorylated by other AGC kinases including RSK and AKT. rpS6 is a component of the 40S ribosomal subunit, and eIF4B is an auxiliary factor that enhances the RNA-unwinding activity of eEF4A. The phosphorylation of rpS6 and eIF4B by AGC kinases significantly promote the translation of mRNA. PDCD4 is reported as pro-apoptotic factor and has been suggested to possess tumor suppressor properties. eEF2K functions as a negative regulator of protein synthesis via phosphorylation and inhibition of eEF2. The phosphorylation of PDCD4 and eEF2K by AGC kinases leads to PDCD4 degradation and the inhibition of eEF2K kinase activity, respectively. Black arrows and red T-bars represent stimulatory and inhibitory signals, respectively

Fig. 3

Schematic representation of PI3K and MAPK signaling to mTORC1. Insulin, growth factors and other stimuli activate mTORC1 signaling through binding and activating RTKs located at the membrane, following which PI3K/AKT and RAS-MAPK integrate these extracellular stimulating signals and convert them into intracellular signals. TSC consists of TSC2 and the scaffolding protein TSC1. The major target of AKT, ERK and RSK involved in the regulation of mRNA translation is TSC2, which is a GAP towards Rheb, and converts Rheb from its active GTP-bound form to the inactive GDP-bound form. Rheb is a small GTPase that stimulates the activation of mTORC1 in its GTP-bound active form. The phosphorylation of TSC2 by AKT, ERK and RSK impedes its GAP activity towards Rheb, resulting in increased Rheb-GTP levels and mTORC1 activation. The major targets of RAS-ERK and RAS-p38 MAPK are RSKs and MNKs. MNKs directly phosphorylate eIF4E on Ser209 which is thought to be the only post-translational modification of eIF4E, this phosphorylation of eIF4E enhances its ability to stimulate mRNA translation. In addition to TSC2, eIF4B, PDCD4 and eEF2K are also the major substrates of RSKs, as illustrated in Fig. 2 and in the text. Black arrows and red T-bars represent stimulatory and inhibitory signals, respectively

Fig. 4

Schematic representation of amino acid, energy and Wnt signaling to mTORC1. Rag GTPases were identified as mediators of amino acid signaling to mTORC1. When an adequate supply of amino acids is present, an active Rag complex consists of GTP-bound Rag A or Rag B and GDP-bound Rag C or Rag D. The Rag complex is able to recruit and anchor mTORC1 to the lysosomal surface which facilitates mTORC1 activation by Rheb. Ragulator functions as a GEF for Rag A/B and also as a scaffold to help anchor the Rag complex to the lysosome. v-ATPase interacts with Ragulator and is required for mTORC1 activity. The GATOR1 complex functions upstream of the Rag complex as a GAP for Rag A/B GTPase and inhibits mTORC1 activity. The GATOR2 complex interacts with and inhibits GATOR1. Sestrin1/2 and CASTOR1/2 are cytosolic leucine and arginine sensor, respectively. The presence of leucine and arginine disrupts the association of Sestrin1/2 and CASTOR1/2 with GATOR2, resulting in the elimination of their inhibition towards GATOR2. SLC38A9 is an important lysosomal arginine sensor and amino acid transporter that directly interacts with Ragulator. FLCN and its binding partner FNIP2 were identified as Rag-interacting proteins with GAP activity for Rag C/D, but not for Rag A/B. Reduction in oxygen or energy levels are sensed by AMPK which can be activated by upstream kinase LKB1 under the conditions of the increased intracellular AMP/ATP and ADP/ATP ratios. The activated AMPK phosphorylates TSC2 and enhances its GAP activity towards Rheb-GTP, finally resulting in the inhibition of mTORC1 activity. Hypoxic stress also stabilizes the transcription factor HIF1α which drives the expression of REDD1. The latter is a negative regulator of mTORC1 activity. Additionally, the activated Wnt signaling pathway stimulates mTORC1 activity via GSK3β repression. Black arrows and red T-bars represent stimulatory and inhibitory signals, respectively

Fig. 5

The direct inhibitors of translation apparatus. The structures of compounds are derived from PubChem. BTdCPU is an activator of HRI which can phosphorylate eIF2α. Salubrinal and guanabenz are inhibitors of phosphatase and inhibit eIF2α dephosphorylation. NSC119889 and NSC119893 are direct inhibitors of eIF2-GTP-Met-tRNAi^Met ternary complex and prevent the binding of tRNAi^Met to eIF2. Hippuristanol, pateamine A and silvestrol are inhibitors of eIF4A. Elatol is an eIF4A-specific inhibitor. 4EGI-1, 4E1RCat and 4E2RCat are inhibitors of eIF4E-eIF4G association