Abstract
BackgroundOral squamous cell carcinoma (OSCC) is a malignant tumor that may occur anywhere within the oral cavity. The survival rate of OSCC patients has not improved over the past decades due to its heterogeneous etiology, genetic aberrations, and treatment outcomes. We investigated the role of tumor necrosis factor receptor-associated factor 6 (TRAF6) in OSCC cells treated with bortezomib (a proteasome inhibitor) combined with irradiation (IR) treatment.MethodsThe effects of combined treatment in OSCC cells were investigated using assays of cell viability, autophagy, apoptosis, western blotting, and immunofluorescence staining. The ubiquitination of proteins was analyzed by immunoprecipitation. Stable knockdown of TRAF6 in OSCC cells was constructed with lentivirus. The xenograft murine models were used to observe tumor growth.ResultsWe found synergistic effects of bortezomib and IR on the viability of human oral cancer cells. The combination of bortezomib and IR treatment induced autophagic cell death. Furthermore, bortezomib inhibited IR-induced TRAF6 ubiquitination and inhibited TRAF6-mediated Akt activation. Bortezomib reduced TRAF6 protein expression through autophagy-mediated lysosomal degradation. TRAF6 played an oncogenic role in tumorigenesis of human oral cancer cells and oral tumor growth was suppressed by bortezomib and IR treatment. In addition, OSCC patients with expression of TRAF6 showed a trend towards poorer cancer-specific survival when compared with patients without TRAF6 expression.ConclusionsA combination of a proteasome inhibitor, IR treatment and TRAF6 inhibition could be a novel therapeutic strategy in OSCC.
Highlights
Oral squamous cell carcinoma (OSCC) is a malignant tumor that may occur anywhere within the oral cavity
We found an increased ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6) and consequent autophagic degradation in OSCC cells treated with bortezomib alone or in combination with IR (Fig. 3)
In summary, our results suggest that bortezomib enhanced radiosensitivity through suppression of radiationinduced TRAF6-nuclear factor κB (NF-κB) signaling activation
Summary
Oral squamous cell carcinoma (OSCC) is a malignant tumor that may occur anywhere within the oral cavity. The survival rate of OSCC patients has not improved over the past decades due to its heterogeneous etiology, genetic aberrations, and treatment outcomes. We investigated the role of tumor necrosis factor receptor-associated factor 6 (TRAF6) in OSCC cells treated with bortezomib (a proteasome inhibitor) combined with irradiation (IR) treatment. OSCC accounts for over 90% of malignant neoplasms of the oral cavity. Surgical resection is feasible for OSCC patients, but it is not effective for late-stage metastatic tumors; adding chemotherapy, radiotherapy or both (chemoradiotherapy, CRT) as adjuvant or as definitive treatment are acceptable modalities [3]. Within the context of CRT, the optimal dose for OSCC irradiation has not been clearly defined. To diminish the damage to normal tissue, treatment with chemical modifiers as radiosensitizers in combination with lower dose irradiation (IR) may augment its overall
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