eIF4E-eIF4G complex inhibition synergistically enhances the effect of sorafenib in hepatocellular carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Sorafenib shows limited efficacy in hepatocellular carcinoma (HCC) due to low response rates and adverse effects.
• The eukaryotic translation initiation factor 4F (eIF4F) complex, particularly the eIF4E-eIF4G interaction, plays a role in drug resistance.
• Targeting eIF4F may overcome sorafenib resistance in HCC.

Purpose of the Study:

• To investigate whether inhibiting the eIF4E-eIF4G complex can enhance the therapeutic effect of sorafenib in HCC.
• To elucidate the underlying mechanisms of this synergistic effect.

Main Methods:

• Cell viability was assessed using MTT and colony formation assays.
• Apoptosis and cell cycle were analyzed by flow cytometry.
• Protein expression and signaling pathways were examined via Western blot and lentivirus transfection.

Main Results:

• Combined treatment with sorafenib and eIF4E-eIF4G inhibitors (4E1RCat or 4EGI-1) synergistically inhibited HCC cell viability and colony formation.
• The combination therapy induced significantly more early apoptosis by downregulating Bcl-2 expression.
• Sorafenib and eIF4F inhibitors suppressed eIF4E, eIF4G, and phospho-4E-BP1 expression, and inhibited the PI3K-AKT-mTOR signaling pathway.

Conclusions:

• Inhibition of the eIF4E-eIF4G complex synergistically enhances the anti-cancer effects of sorafenib in HCC.
• This combination strategy represents a potential therapeutic approach for improving sorafenib treatment outcomes in HCC.
• Targeting the eIF4F complex may overcome sorafenib resistance and improve patient response.