Modulation of radiosensitivity of thyroid cancer cells by inhibition of NF-κB signaling

Abstract

Nuclear transcription factor-κB (NF-κB) is a transcriptional complex that binds to the κB cis-acting transcriptional activation DNA domain in response to different stresses including ionizing radiation (IR). Activation of NF-κB has been reported to protect cells from TNFα-, chemotherapy- and radiation-induced apoptosis. To overcome the limitation of radiation therapy for thyroid cancers, we first studied the response of the NF-κB cascade to IR in cultured normal human thyroid cells and various thyroid cancer cell lines. Exposure to IR resulted in a dose-dependent increase of p65/p50 heterodimer DNA-binding activity in all types of thyroid cells. Specific inhibitors of NF-κB or dominant-negative mutant IκBα reduced thyroid cancer cell survival after exposure to IR and enhanced IR-induced apoptosis in an undifferentiated thyroid cancer cell line. Tumors harboring mutant IκBα implanted into nude mice exhibited delayed growth rate and increased radiosensitivity. Our results indicate that radiosensitivity of transformed thyroid cells can be increased by inhibition of induction of the active form of NF-κB. We therefore suggest that inhibition of NF-κB could be an effective modality for radiation therapy of advanced human thyroid cancers.