Function of nuclear factor κB in pancreatic cancer metastasis
Purpose: We seek to elucidate the role of constitutive nuclear factor κB (NFκB) activity in human pancreatic cancer cells. We have demonstrated that the transcription factor NFκB is activated constitutively 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 NFκB plays a critical role in development of pancreatic adenocarcinoma. Experimental Design: By pooling all of the puromycin resistant clones after inhibitor of nuclear factor-κB phosphorylation mutant (IκBαM) retroviral infection, we generated pancreatic tumor cell lines that express a IκBαM (S32, 36A) that blocks NFκB activity. Inhibition of metastatic phenotype was assayed in an orthotopic nude mouse model. NFκB activity was determined by electrophoretic mobility shift assay, and the expression of NFKB downstream target genes was analyzed by Northern, Western, and immunohistochemical analyses. Results: We showed that inhibiting constitutive NFκB activity by expressing IκBαM suppresses liver metastasis, but not tumorigenesis, from the metastatic human pancreatic tumor cell line AsPc-1 in an orthotopic nude mouse model. Furthermore, inhibiting NFκB activation by expressing IκBαM significantly reduced in vivo expression of a major proangiogenic molecule, vascular endothelial growth factor, and, hence, decreased neoplastic angiogenesis. Inhibiting NFκB activation by expressing IκBαM and using pharmacologic NFκB inhibitor PS-341 also significantly reduced cytokine-induced vascular endothelial growth factor and interleukin-8 expression in AsPc-1 pancreatic cancer cells. Conclusion: These results demonstrated that the inhibition of NFκB signaling can suppress the angiogenic potential and metastasis of pancreatic cancer, and suggest that the NFκB signaling pathway is a potential target for anticancer agents.
Fujioka, S; Sclabas, GM; Schmidt, C; Frederick, WA; Dong, QG; Abbruzzese, JL; Evans, DB; Baker, C; Chiao, PJ
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