Abstract
BACKGROUND: Nuclear factor-kappaB (NF-kappaB) is constitutively activated in many cancers and plays a key role in promoting cell proliferation, survival, and invasion. Our understanding of NF-kappaB signaling in thyroid cancer, however, is limited. In this study, we have investigated the role of NF-kappaB signaling in thyroid cancer cell proliferation, invasion, and apoptosis using selective genetic inhibition of NF-kappaB in advanced thyroid cancer cell lines. RESULTS: Three pharmacologic inhibitors of NF-kappaB differentially inhibited growth in a panel of advanced thyroid cancer cell lines, suggesting that these NF-kappaB inhibitors may have off-target effects. We therefore used a selective genetic approach to inhibit NF-kappaB signaling by overexpression of a dominant-negative IkappaBalpha (mIkappaBalpha). 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 TNFalpha-induced apoptosis was observed in all cell lines, likely through an NF-kappaB-dependent mechanism. Inhibition of NF-kappaB by mIkappaBalpha sensitized a subset of cell lines to TNFalpha-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-kappaB inhibition by mIkappaBalpha 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 expression in all cell lines tested. CONCLUSIONS: These data indicate that selective inhibition of NF-kappaB 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-kappaB signaling alone. Instead, our findings suggest that other important molecular processes play a critical role in defining the extent of NF-kappaB function within cancer cells.