Inhibition of nuclear factor-kappa B differentially affects thyroid cancer cell growth, apoptosis, and invasion

Molecular Cancer

Research

Kevin T Bauerle¹  Rebecca E Schweppe²  Bryan R Haugen² 

[1] Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado - Anschutz Medical Campus, Research Complex I, PO Box 6511, South Tower, Mail Stop 8106, 12801 East 17th Avenue, 80045, Aurora, CO, USA;Program in Cancer Biology, University of Colorado - Anschutz Medical Campus, Research Complex I, South Tower, Mail Stop 8104, 12801 East 17th Avenue, 80045, Aurora, CO, USA;Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado - Anschutz Medical Campus, Research Complex I, PO Box 6511, South Tower, Mail Stop 8106, 12801 East 17th Avenue, 80045, Aurora, CO, USA;University of Colorado Cancer Center, 80045, Aurora, CO, USA;

关键词: Thyroid Cancer;    Oral Squamous Cell Carcinoma;    Papillary Thyroid Cancer;    BRAF V600E Mutation;    Thyroid Cancer Cell;   

DOI  :  10.1186/1476-4598-9-117

 received in 2010-03-08, accepted in 2010-05-21,  发布年份 2010

来源: Springer

【 摘 要 】

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

【 授权许可】

Unknown   
© Bauerle et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.