Relevance of Translation Initiation in Diffuse Glioma Biology and its Therapeutic Potential

Abstract

Cancer cells are continually exposed to environmental stressors forcing them to adapt their protein production to survive. The translational machinery can be recruited by malignant cells to synthesize proteins required to promote their survival, even in times of high physiological and pathological stress. This phenomenon has been described in several cancers including in gliomas. Abnormal regulation of translation has encouraged the development of new therapeutics targeting the protein synthesis pathway. This approach could be meaningful for glioma given the fact that the median survival following diagnosis of the highest grade of glioma remains short despite current therapy. The identification of new targets for the development of novel therapeutics is therefore needed in order to improve this devastating overall survival rate. This review discusses current literature on translation in gliomas with a focus on the initiation step covering both the cap-dependent and cap-independent modes of initiation. The different translation initiation protagonists will be described in normal conditions and then in gliomas. In addition, their gene expression in gliomas will systematically be examined using two freely available datasets. Finally, we will discuss different pathways regulating translation initiation and current drugs targeting the translational machinery and their potential for the treatment of gliomas.

Keywords: IRES; cap-dependent; gliomas; protein synthesis; translation.

Figure 1

Schematic representation of cap-dependent translation initiation. (a) During the first step of translation, the eukaryotic translation initiation factor (eIF) 4F (eIF4F) complex is formed and associates with mRNAs. eIF4F is composed of three subunits (represented in green): eIF4E which binds the 7-methylguanosine 5′-triphosphate (m7GTP) cap structure present on the 5’ end of the mRNA; eIF4G which is a scaffold protein and eIF4A which is an RNA helicase ATP-dependent protein unwinding mRNA during translation. The formation of eIF4F complex can be inhibited by programmed cell death 4 (PDCD4) and eIF4E-binding proteins (4E-BPs) which bind eIF4A and eIF4E, respectively. (b) During the second step of cap-dependent translation, the small ribosomal subunit (40S, red) associated with eIF1, eIF1A, eIF3 and eIF5 interacts with the ternary complex constituted of eIF2, a switch-protein bound to guanosine triphosphate (GTP) and the initiator methionyl-transfer RNA (Met-tRNAi). Together they form the 43S preinitiation complex (43S PIC). eIF2 is a heterotrimeric structure composed of three subunits (α, β and γ). At this stage, poly(A) binding protein (PABP, an RNA-binding protein) binds eIF4G and the 3’ poly(A) tail to induce mRNA circularization. eIF4B also interacts with eIF4A to stabilize unwounded mRNA and stimulate eIF4A RNase and helicase activities. (c) The 43S PIC associates with the eIF4F complex to form the 48S PIC before scanning the mRNA until it reaches and recognizes the start codon (AUG), and Met-tRNAi binds the peptidyl (P) site of the ribosome. The 60S ribosomal subunit associated with eIF6 will then be recruited. (d) The 60S binds the 40S which triggers eIF2-GTP hydrolysis into guanosine diphosphate bound (GDP), leading to eIFs release and the formation of the 80S initiation complex. At this stage, the initiation complex is fastened on the mRNA and the elongation begins. The aminoacyl (A) and the exit (E) sites present in the ribosome correspond to the sites where a second tRNA with its amino acid enters the ribosome and the amino acid depleted tRNA exits the ribosome, respectively. Finally, once the ternary complex has been released, eIF2B frees up eIF5 and restores eIF2-GDP into eIF2-GTP.

Figure 2

Regulation of eIF4F complex formation by PI3K/Akt/mTOR, MAPK/MNK, and AMPK pathways and drugs targeting these pathways. mTOR, a downstream effector of PI3K/Akt pathway, is a serine/threonine kinase which is the core of two protein complexes: mTORC1 and mTORC2. mTORC1 phosphorylates 4E-BP and the S6K1 kinase. 4E-BP phosphorylation leads to 4E-BP1/eIF4E dissociation and consequently formation of the eIF4F complex. S6K1 phosphorylation leads to its activation which in turn phosphorylates eIF4G, eIF4B, and PDCD4. Once phosphorylated, PDCD4 is degraded thus freeingeIF4A which can then join the eIF4F complex. Phosphorylated eIF4B stabilizes unwounded mRNA and stimulates eIF4A RNase and helicase activities. Phosphorylated S6K1 also inhibits the PI3K/Akt pathway by a feedback loop (dotted red line). mTORC2 can phosphorylate and activate Akt which inhibits IRES-dependent translation. MNKs are downstream effectors of the MAPK/MNK pathway able to phosphorylate eIF4E which then promotes mRNA translation initiation. Finally, the AMPK pathway modulates protein synthesis by inhibiting mTORC1 and consequently blocking 4E-BP/eIF4E dissociation and eIF4F complex formation. Drugs acting as activators or inhibitors of these different pathways are represented in green or in red, respectively. mTOR—mechanistic target of rapamycin; PI3K—phosphoinositide 3-kinase; Akt—protein kinase B; mTORC—mechanistic target of rapamycin complex; 4E-BP—eukaryotic translation initiation factor 4E-binding protein; S6K1—S6 kinase 1; eIF—eukaryotic initiation factor; PDCD4—programmed cell death 4; IRES—internal ribosome entry site; MAPK—Mitogen-activated protein kinase (MAPK); MNK—MAPK interacting protein kinases; AMPK—AMP-activated protein kinase. Phosphorylation is represented by a yellow sphere containing the letter P.