INF-γ sensitizes head and neck squamous cell carcinoma cells to chemotherapy-induced apoptosis and necroptosis through up-regulation of Egr-1

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Acquired resistance to standard chemotherapy accounts for most of treatment failure. Here we demonstrate that Interferon-gamma (INF-gamma) may up-regulate Egr-1 gene expression in HNSCC cell line SCC-25. Forced expression of Egr-1 sensitizes SCC-25 cells to chemotherapy-induced apoptosis and necroptosis, a novel form of programmed cell death. Egr-1 up-regulation also significantly increases the production of Thrombospondin-1 (TSP-1), a matricellular glycoprotein which has been described to induce cell death in HNSCC. Moreover, INF-gamma-induced sensitization of cells to chemotherapy-mediated cell death and TSP-1 production could be markedly abolished by Egr-1 silencing. The present investigation provides the first evidence that INF-gamma may sensitize HNSCC cells to chemotherapy-induced apoptosis and necroptosis through up-regulation of Egr-1. These data support the combination use of INF-gamma and cytotoxic drugs for HNSCC Therapy.