Abstract
We have demonstrated that nuclear factor-κB (NF-κB) is constitutively activated in human pancreatic adenocarcinoma and human pancreatic cancer cell lines but not in normal pancreatic tissues or in immortalized, nontumorigenic pancreatic epithelial cells, suggesting that NF-κB plays a critical role in the development of pancreatic adenocarcinoma. To elucidate the role of constitutive NF-κB activity in human pancreatic cancer cells, we generated pancreatic tumor cell lines that express a phosphorylation defective IκBα (S32, 36A) (IκBαM) that blocks NF-κB activity. In this study, we showed that inhibiting constitutive NF-κB activity by expressing IκBαM suppressed the tumorigenicity of a nonmetastatic human pancreatic cancer cell line, PANC-1, in an orthotopic nude mouse model. Immunohistochemical analysis showed that PANC-1-derived tumors expressed vascular endothelial growth factor (VEGF) and induced angiogenesis. Inhibiting NF-κB signaling by expressing IκBαM significantly reduced expression of Bcl-xL and Bcl-2. The cytokine-induced expression of VEGF and Interleukin-8 in PANC-1 cells is also decreased. Taken together, these results suggest that the inhibition of NF-κB signaling can suppress tumorigenesis of pancreatic cancer cells and that the NF-κB signaling pathway is a potential target for anticancer agents.
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Acknowledgements
We thank Mariann Crapanzano for editorial assistance. This work was supported in part by grants CA73675, CA78778, and CA 75517 from the National Cancer Institute (NCI), and a grant from the Lockton Fund for Pancreatic Cancer Research. WAF is a recipient of the NCI T32 Training Grant Fellowship, and GMS is a recipient of a Fellowship of the Cancer League of Bern, Switzerland.
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Fujioka, S., Sclabas, G., Schmidt, C. et al. Inhibition of constitutive NF-κB activity by IκBαM suppresses tumorigenesis. Oncogene 22, 1365–1370 (2003). https://doi.org/10.1038/sj.onc.1206323
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DOI: https://doi.org/10.1038/sj.onc.1206323
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