Nuclear factor-kappa B (NF-kappa B) is constitutively activated in many cancers and plays a key role in promoting cell proliferation, survival, and invasion. Our understanding of NF-kappa B signalling in thyroid cancer, however, is limited. In this study, we have investigated the role of NF-kappa B signalling on thyroid cancer cell proliferation, invasion, and apoptosis using selective genetic inhibition of NF-kappa B in advanced thyroid cancer cell lines.

Three pharmacologic inhibitors of NF-kappa B differentially inhibited growth in a panel of advanced thyroid cancer cell lines, suggesting that these NF-kappa B inhibitors may have off-target effects. We therefore used a selective genetic approach to inhibit NF-kappa B signalling by overexpression of a dominant-negative I kappa B alpha (mutant I kappa B alpha). These studies revealed decreased cell growth in only one of five thyroid cancer cell lines (8505C), which occurred through a block in the S-G2/M transition. Resistance to TNF alpha-induced apoptosis was observed in all cell lines, likely through an NF-kappa B-dependent mechanism. Inhibition of NF-kappa B by mutant I kappa B alpha sensitized a subset of cell lines to TNF alpha-induced apoptosis. Sensitive cell lines displayed sustained activation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway, defining a potential mechanism of response. Finally, NF-kappa B inhbition by mutant I kappa B alpha expression differentially reduced thyroid cancer cell invasion in these thyroid cancer cell lines. Sensitive cell lines demonstrated approximately a two-fold decrease in invasion, which was associated with differential expression of MMP-13. MMP-9 was reduced by mIkappaBalpha in all cell lines tested.

These data indicate that selective inhibition of NF-kappa B represents an attractive therapeutic target for the treatment of advanced thyroid. However, it is apparent that global regulation of thyroid cancer cell growth and invasion is not achieved by NF-kappa B signalling alone. Instead, our findings suggest that other important molecular processes play a critical role in defining the extent of NF-kappa B function within cancer cells.

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