Inhibition of EIF2α Dephosphorylation Decreases Cell Viability and Synergizes with Standard-of-Care Chemotherapeutics in Head and Neck Squamous Cell Carcinoma

Area of Science:

• Molecular Biology
• Oncology
• Biochemistry

Background:

• Drug resistance frequently causes treatment failure in head and neck squamous cell carcinoma (HNSCC).
• Targeting fundamental cellular processes like translation offers a strategy to overcome resistance.
• Eukaryotic translation initiation factor 2α (EIF2α) regulates protein synthesis and stress responses.

Purpose of the Study:

• To evaluate EIF2α expression and phosphorylation in HNSCC.
• To investigate the therapeutic potential of inhibiting EIF2α dephosphorylation using salubrinal in HNSCC.
• To assess salubrinal's efficacy alone and in combination with standard chemotherapeutics.

Main Methods:

• Analysis of RNA and proteomics data for EIF2α expression.
• Immunohistochemical staining and immunoblot analyses of HNSCC tissues and cell lines.
• In vitro studies using salubrinal on HNSCC cells and patient-derived 3D tumor spheres (PD3DS), including viability, flow cytometry, and clonogenic assays.

Main Results:

• Elevated EIF2α expression and phosphorylation were observed in HNSCC compared to normal tissues, increasing with disease progression.
• Salubrinal treatment reduced HNSCC cell viability, clonogenic survival, and impaired cell cycle progression.
• Salubrinal demonstrated synergistic effects with cisplatin, 5-fluorouracil, bleomycin, and proteasome inhibitors, and reduced PD3DS viability.

Conclusions:

• Pharmacological inhibition of EIF2α dephosphorylation is a promising therapeutic strategy for HNSCC.
• Salubrinal effectively targets HNSCC cells and enhances the efficacy of conventional treatments.
• Targeting EIF2α dephosphorylation represents a novel approach to combat drug resistance in HNSCC.