Abstract
Simple SummaryGliomas are brain tumors with currently limited therapy options. Glioma growth and proliferation is regulated by the mTOR pathway together with eukaryotic initiation factors (eIFs). In this work we show a profound basic characterization of eIFs in human gliomas and demonstrate increased mRNA and protein expressions of several eIFs in gliomas compared to healthy control brain tissue. Moreover, increased eIF3I and eIF4H levels seem to have a negative influence on the survival of patients. Our work suggests eIF3I and eIF4H as potential targets for future glioma therapy.Glioblastoma (GBM) is an utterly devastating cerebral neoplasm and current therapies only marginally improve patients’ overall survival (OS). The PI3K/AKT/mTOR pathway participates in gliomagenesis through regulation of cell growth and proliferation. Since it is an upstream regulator of the rate-limiting translation initiation step of protein synthesis, controlled by eukaryotic initiation factors (eIFs), we aimed for a profound basic characterization of 17 eIFs to identify potential novel therapeutic targets for gliomas. Therefore, we retrospectively analyzed expressions of mTOR-related proteins and eIFs in human astrocytoma samples (WHO grades I–IV) and compared them to non-neoplastic cortical control brain tissue (CCBT) using immunoblot analyses and immunohistochemistry. We examined mRNA expression using qRT-PCR and additionally performed in silico analyses to observe the influence of eIFs on patients’ survival. Protein and mRNA expressions of eIF3B, eIF3I, eIF4A1, eIF4H, eIF5 and eIF6 were significantly increased in high grade gliomas compared to CCBT and partially in low grade gliomas. However, short OS was only associated with high eIF3I gene expression in low grade gliomas, but not in GBM. In GBM, high eIF4H gene expression significantly correlated with shorter patient survival. In conclusion, we identified eIF3I and eIF4H as the most promising targets for future therapy for glioma patients.
Highlights
Gliomas are the most common primary brain tumors originating from glial cells
Since it is an upstream regulator of the rate-limiting translation initiation step of protein synthesis, controlled by eukaryotic initiation factors, we aimed for a profound basic characterization of 17 eIFs to identify potential novel therapeutic targets for gliomas
We aimed to confirm the activation of the PI3K/AKT/mechanistic target of rapamycin (mTOR) pathway using immunoblot analyses (Figure 1)
Summary
Gliomas are the most common primary brain tumors originating from glial cells. Current treatment strategies for highly malignant gliomas include surgical resection followed by adjuvant radio-chemotherapy [2]. Less commonly distant, recurrence is observed in most patients following initial resection and chemo-/radiotherapy, exemplifying the tumor’s infiltrative nature and heterogeneity [5]. The PI3K/AKT/mechanistic target of rapamycin (mTOR) signaling pathway is a major survival pathway and has already been extensively studied in GBM. Deregulation of PI3K/AKT/mTOR signaling seems to be one of the key players driving gliomagenesis [6]. Common mutations detected in GBM induce a constitutive activation of this pathway [7]. The PI3K/AKT/mTOR pathway regulates the rate-limiting step of protein synthesis [8]
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