Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy-mediated TRAF6 oncoprotein degradation

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Oral squamous cell carcinoma (OSCC) presents a significant challenge due to its complex nature and poor survival rates.
• The role of tumor necrosis factor receptor-associated factor 6 (TRAF6) in OSCC treatment remains incompletely understood.
• Investigating novel therapeutic targets is crucial for improving outcomes in OSCC patients.

Purpose of the Study:

• To evaluate the efficacy of combining bortezomib (a proteasome inhibitor) with irradiation (IR) in OSCC cells.
• To elucidate the role of TRAF6 in the response to combined bortezomib and IR treatment.
• To explore the potential of targeting TRAF6 as a therapeutic strategy for OSCC.

Main Methods:

• Cell viability, autophagy, and apoptosis assays were performed on OSCC cells.
• Western blotting, immunofluorescence staining, and immunoprecipitation were used to analyze protein expression and ubiquitination.
• Stable TRAF6 knockdown and xenograft murine models were employed to assess tumor growth inhibition.

Main Results:

• Combined bortezomib and IR treatment demonstrated synergistic effects on OSCC cell viability, inducing autophagic cell death.
• Bortezomib inhibited IR-induced TRAF6 ubiquitination and Akt activation, reducing TRAF6 expression via autophagy-mediated lysosomal degradation.
• TRAF6 exhibited an oncogenic role in OSCC tumorigenesis, and its inhibition, alongside bortezomib and IR, suppressed tumor growth. Higher TRAF6 expression correlated with poorer survival in OSCC patients.

Conclusions:

• The combination of bortezomib, IR, and TRAF6 inhibition presents a promising novel therapeutic strategy for OSCC.
• Targeting TRAF6 may enhance the effectiveness of proteasome inhibitors and irradiation in managing oral cancer.
• Further research into this combined therapeutic approach could lead to improved patient outcomes.