Chemotherapy with 5-fluorouracil (5-FU) is commonly used in combination therapy for esophageal squamous cell carcinoma (ESCC), but its efficacy is limited in certain patients. Recent studies suggest that constitutive activation of nuclear factor-κB (NF-κB) has a critical role in tumorigenesis and is associated with poor prognosis and resistance to chemoradiation therapy in many types of human cancers. In the present study, we evaluated the effect of small interfering RNA targeting NF-κB (NF-κB siRNA) combined with 5-FU on the proliferation of two cell lines of cultured ESSCs. Immunofluorescence and immunoblot analyses revealed that the NF-κB protein was localized mostly in the cytoplasm of ESCCs. When cultured ESCCs were exposed to tumor necrosis factor-α, NF-κB was transferred to the nucleus and activated. ESCCs with activated NF-κB had poor sensitivity to 5-FU. When cells were transfected with NF-κB siRNA, the levels of NF-κB protein were significantly decreased in the cytoplasm and the nucleus. Transcriptional activity of NF-κB was significantly suppressed in cells treated with 5-FU and NF-κB siRNA compared to cells treated with 5-FU alone. 5-FU consistently suppressed proliferation of ESCCs in a dose-dependent manner, and this effect was significantly enhanced when combined with NF-κB siRNA. These results suggest that combination therapy of 5-FU with NF-κB siRNA may provide a new therapeutic option for ESCC.

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