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.

Characterizing the Genomic Profile in High-Grade Gliomas: From Tumor Core to Peritumoral Brain Zone, Passing through Glioma-Derived Tumorspheres

“…We evidenced that a very large number of genes involved in gains and shared between TCs and GSCs belong to the GO term cellular component, particularly extracellular space, extracellular region and membrane, indicating a strong involvement in intercellular signaling. Interestingly, several gained genes shared between at least two datasets were reported in the literature as overexpressed in high-grade gliomas, associated with poor prognosis, or in any case, involved in canonical pathways of GBM ( EIF2AK1 , FTL , SRC , GNG8 , GNG11 , GNG7 , FZD9 , GNB2 , TGM2 ) [ 45 , 46 , 47 , 48 , 49 ]. Conversely, only one lost gene, AKR1C2 , shared between at least two datasets, was reported as downregulated and associated with high-risk-score glioma in the REMBRANDT data set [ 50 ].…”

The dark side of mRNA translation and the translation machinery in glioblastoma

“…The mRNAs of all eIF3 subunits, except subunit k, are significantly overexpressed in GB ( Digregorio et al, 2019 ), and the levels of eIF3 proteins are increased in high-grade gliomas ( Krassnig et al, 2021 ). These observations are important because the following eIF3 subunits have been involved in GB progression ( Figure 3 ).…”

“…eIF4G activity has been strongly related to breast, lung, and head and neck cancers ( Wagner et al, 2014 ). Further metadata studies from the brain datasets REMBRANDT ( Gusev et al, 2018 ) and the Cancer Genome Atlas (TCGA) ( Verhaak et al, 2010 ) revealed that eIF4G and eIF4G2 , but not eIF4G3 mRNAs are highly overexpressed in different types of GB ( Digregorio et al, 2019 ). However, the relevance of this observation in cancer is unknown.…”

Molecular and Cellular Mechanisms of Glioblastoma

“…The six reviews touch on interesting topics, such as immunotherapy [1,2], extracellular vesicles [3], energy metabolism [4], translational machinery [5] and the Hippo signaling pathway [6] in glioblastoma.…”

“…Targeting the translational machinery is becoming a new field of research in cancer biology. Digregorio et al [5] describe cap-dependent and cap-independent translation initiation mechanisms, and indicate some of the targets, e.g., members of the eIF3 family or 4E-BP1, that, if knocked down, could favor the inhibition of the two forms of translation control.…”