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Expression of a Dominant-Negative Mutant Inhibitor-B of Nuclear Factor-B in Human Head and Neck Squamous Cell Carcinoma Inhibits Survival, Proinflammatory Cytokine Expression, and Tumor Growth in Vivo¹

Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders [D. D., Z. C., G. D., F. G. O., J. S. W., C. V. W.] and Laboratory of Immunoregulation, National Institute of Immunology, Allergy, and Infectious Diseases [K. B., U. S.], NIH, Bethesda, Maryland 20892

We demonstrated recently that constitutive expression of proinflammatory cytokines interleukin (IL)-1, IL-6, IL-8, and granulocyte- macrophage colony-stimulating factor in head and neck squamous cell carcinoma is correlated with activation of transcription factor nuclear factor (NF)-B/Rel A (p50/p65), which binds the promoter region within each of the genes encoding this repertoire of cytokines. NF-B can be activated after signal-dependent phosphorylation and degradation of inhibitor-B and has been reported to promote cell survival and growth. In the present study, we expressed a phosphorylation site mutant of inhibitor-B (IBM) in head and neck squamous cell carcinoma lines UM-SCC-9, -11B, and -38 to determine the effect of inhibition of NF-B on cytokine expression, cell survival in vitro, and growth in vivo. After transfection with IBM, only a few UM-SCC-9 clones were obtained that stably expressed the mutant IB, suggesting that expression of a mutant IB may affect survival of the transfected UM-SCC cell lines. After cotransfection of IBM with a Lac-Z reporter, we found that the number of surviving ß-galactosidase-positive cells in the three cell lines was reduced by 70–90% when compared with controls transfected with vector lacking the insert. In UM-SCC-9 cells that stably expressed IBM, inhibition of constitutive and tumor necrosis factor- induced NF-B activation, and production of all four cytokines was observed. Although UM-SCC-9 IBM-transfected cells proliferated at the same rate as vector-transfected cells in vitro, a significant reduction in growth of tumor xenografts was observed in SCID mice in vivo. The decreased growth of UM-SCC-9 IBM-transfected tumor cells accompanied decreased immunohistochemical detection of the activated form of NF-B in situ. These results provide evidence that NF-B and IB play an important role in survival, constitutive and inducible expression of proinflammatory cytokines, and growth of squamous cell carcinoma. NF-B could serve as a potential target for therapeutic intervention against cytokine and other immediate-early gene responses that contribute to the survival, growth, and pathogenesis of these cancers.

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