Expression and therapeutic potential of the eukaryotic initiation factor 2α (eIF2α) in head and neck squamous cell carcinomas (HNSCC)

Introduction:

The eukaryotic Initiation Factors (eIFs) regulate the rate-limiting phase of proteinsynthesis. They are deregulated in many types of cancer are known to play a role in oncogenesis. eIF2α facilitates the binding of fMET-tRNA to the ribosome. Active only in its non-phosphorylated form, it is inhibited by 4 stress-dependent kinases. The activity of eIF2α can be inhibited by the selective phosphatase inhibitor- salubrinal.

The aim of this study was to determine the pattern of expression of eIFs in head and neck squamous cell carcinomas (HNSCC) and assess, whether they could become potential therapy targets.

Methods:

Multivariate survival analysis of mRNA data (source TCGA, PanCancer Atlas) from 528 patients was performed; followed by immunohistochemistry (IHC) on a panel (n = 105) of HNSCC. Further, experiments on laryngeal cancer cell lines were carried out to examine the effects of selective inhibition of eIF2α with salubrinal on cell viability, as well as chemosensitivity testing on a panel of 3D-patient-derived organoids (PDO).

Results:

Patients with high expression of eIF2α and low expression of its kinases feature lower overall survival. The IHC stain of HNSCC samples showed high expression of eIF2α in HNSCC.

Further, we saw a decrease in cell viability of about 40% after treatment with salubrinal in all cell lines. Chemosensitivity testing on 3DPD-models showed a dose-dependent decrease in cell viability and an average IC50 von 56µM (Range 16 – 158µM).

Conclusion:

The prognostic relevance of mRNA-Expression, as well as the decrease in cell viability in cell culture and in PDOs suggests a therapeutic potential of eIF2α-complex Inhibition.

Publication History

Publication Date:
23 April 2019 (online)