Inhibition of constitutive NF-κB activity by IκBαM suppresses tumorigenesis

We have demonstrated that nuclear factor-kappaB (NF-kappaB) 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-kappaB plays a critical role in the development of pancreatic adenocarcinoma. To elucidate the role of constitutive NF- kappaB activity in human pancreatic cancer cells, we generated pancreatic tumor cell lines that express a phosphorylation defective IkappaBalpha (S32, 36A) (IkappaBalphaM) that blocks NF-kappaB, activity. In this study, we showed that inhibiting constitutive NF-kappaB activity by expressing IkappaBalphaM 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-kappaB signaling by expressing licBaM significantly reduced expression of Bcl-x(L) 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-kappaB signaling can suppress tumorigenesis of pancreatic cancer cells and that the NF-kappaB signaling pathway is a potential target for anticancer agents.