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Inhibition of Nuclear Factor-B Cascade Potentiates the Effect of a Combination Treatment of Anaplastic Thyroid Cancer Cells

Departments of Molecular Medicine (D.S., H.N., S.Y.) and International Health and Radiation Research (V.S., S.Y.), Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, and Takashi Nagai Memorial International Hibakusha Medical Center (A.O., S.Y.), Nagasaki University Hospital, Nagasaki 852-8523, Japan

Address all correspondence and requests for reprints to: Hiroyuki Namba, M.D., Ph.D., Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. E-mail: namba{at}net.nagasaki-u.ac.jp.

Nuclear transcription factor-B (NF-B) is a transcriptional complex that is rapidly activated in the course of an immediate early response of cells after exposure to different stresses including ionizing radiation (IR). To overcome the limitation of radiation therapy for thyroid cancers, we studied the response of the NF-B 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 DNA-binding activity of p65 and p50 subunits in all types of thyroid cells. Specific inhibitors of NF-B or phosphorylation deficient mutant inhibitory protein IB reduced thyroid cancer cell survival after exposure to IR and enhanced IR-induced cell death in a model undifferentiated thyroid cancer cell line. Tumors harboring mutant IB implanted into nude mice exhibited delayed growth rate and increased radiosensitivity. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling and annexinV-propidium iodide staining revealed the increase of radiation-induced apoptosis in the cells with inhibited NF-B signaling. Our results indicate that radiosensitivity of transformed thyroid cells is due in part to elevated basal activity and rapid induction of the active form of NF-B. We therefore suggest that inhibition of NF-B could be an effective modality for radiation therapy of advanced human thyroid cancers.

This work was supported by a Grant-in-Aid for General Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (to H.N., Grant 13671158; to V.S., Grant 14380256; to S.Y., Grant 12576020).

Abbreviations: ATC, Anaplastic thyroid cancer; DTT, dithiothreitol; FBS, fetal bovine serum; IAP, inhibitor of apoptosis; IB, inhibitory protein B; IR, ionizing radiation; mutIB, mutant IB; NF-B, nuclear transcription factor-B; PARP, poly-(ADP-ribose) polymerase; PI, propidium iodide.

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