Insulin-like growth factor binding protein 3 promotes expression previously demonstrated to enhance lymph node metastasis of oral squamous cell carcinoma cells. However, OSCC patients with high IGFBP3 expression had a better prognostic outcome than those with low IGFBP3 expression. We found that ectopic IGFBP3 expression enhanced the ionizing radiation -induced cell-killing effect. In vivo, IGFBP3 reduced tumor growth and increased apoptotic signals in nude mice treated with IR. Combined with IR, ectopic IGFBP3 expression induced mitochondria-dependent cell apoptosis. IGFBP3-induced cell death as evidenced by mitochondria destruction and increase of reactive ROS production. IGFBP3 expression enhanced NK- κ B activation and downstream cytokine expression. IGFBP3-mediated ROS production was reduced by the NK- κ B inhibitor BMS-345541, while exogenous IL-6 rescued the NF- κ B-inhibited, IGFBP3-mediated ROS production. Collectively, our data demonstrated that IGFBP3, a penitential radiosensitive biomarker, promoted OSCC cell death under IR via positive feedback of ROS production by inducing NF- κ B activation and cytokine expression.
