Expression of a dominant-negative mutant inhibitor-κBα of nuclear factor-κB in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo

Dianne C. Duffey, Zhong Chen, Gang Dong, Frank G. Ondrey, Jeffery S. Wolf, Keith Brown, Ulrich Siebenlist, Carter Van Waes

Research output: Contribution to journalArticlepeer-review

248 Scopus citations

Abstract

We demonstrated recently that constitutive expression of proinflammatory cytokines interleukin (IL)-1α, 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)- κB/Rel A (p50/p65), which binds the promoter region within each of the genes encoding this repertoire of cytokines. NF-κB can be activated after signal- dependent phosphorylation and degradation of inhibitor-κBα and has been reported to promote cell survival and growth. In the present study, we expressed a phosphorylation site mutant of inhibitor-κBα (IκBαM) in head and neck squamous cell carcinoma lines UM-SCC-9, -11B, and -38 to determine the effect of inhibition of NF-κB on cytokine expression, cell survival in vitro, and growth in vivo. After transfection with IκBαM, only a few UM- SCC-9 clones were obtained that stably expressed the mutant IκB, suggesting that expression of a mutant IκBα may affect survival of the transfected UM- SCC cell lines. After cotransfection of IκBαM with a Lac-Z reporter, we found that the number of surviving β-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 IκBαM, inhibition of constitutive and tumor necrosis factor-α induced NF-κB activation, and production of all four cytokines was observed. Although UM-SCC-9 IκBαM-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 IκBαM-transfected tumor cells accompanied decreased immunohistochemical detection of the activated form of NF-κB in situ. These results provide evidence that NF-κB and IκBα play an important role in survival, constitutive and inducible expression of proinflammatory cytokines, and growth of squamous cell carcinoma. NF-κB 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.

Original languageEnglish (US)
Pages (from-to)3468-3474
Number of pages7
JournalCancer Research
Volume59
Issue number14
StatePublished - Jul 15 1999

Fingerprint Dive into the research topics of 'Expression of a dominant-negative mutant inhibitor-κBα of nuclear factor-κB in human head and neck squamous cell carcinoma inhibits survival, proinflammatory cytokine expression, and tumor growth in vivo'. Together they form a unique fingerprint.

Cite this