Inhibition of constitutive NF-kappa B activity by I kappa B alpha M suppresses tumorigenesis.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print Cited Medium: Print ISSN: 0950-9232 (Print) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE

Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-

Adenocarcinoma/*pathology ; I-kappa B Proteins/*physiology ; NF-kappa B/*physiology ; Neovascularization, Pathologic/*prevention & control ; Pancreatic Neoplasms/*pathology; Adenocarcinoma/blood supply ; Adenocarcinoma/metabolism ; Animals ; Endothelial Growth Factors/biosynthesis ; Gene Expression Regulation, Neoplastic ; Genes, Reporter ; Genes, bcl-2 ; Humans ; I-kappa B Proteins/genetics ; Intercellular Signaling Peptides and Proteins/biosynthesis ; Interleukin-8/biosynthesis ; Interleukin-8/genetics ; Luciferases/biosynthesis ; Luciferases/genetics ; Lymphokines/biosynthesis ; Mice ; Mice, Nude ; Mutation ; NF-KappaB Inhibitor alpha ; NF-kappa B/antagonists & inhibitors ; Neoplasm Proteins/biosynthesis ; Neoplasm Proteins/genetics ; Neoplasm Transplantation ; Neovascularization, Pathologic/genetics ; Pancreatic Neoplasms/blood supply ; Pancreatic Neoplasms/metabolism ; Phosphorylation ; Promoter Regions, Genetic/genetics ; Protein Processing, Post-Translational/genetics ; Proto-Oncogene Proteins c-bcl-2/biosynthesis ; Proto-Oncogene Proteins c-bcl-2/genetics ; Recombinant Fusion Proteins/biosynthesis ; Recombinant Fusion Proteins/physiology ; Tumor Cells, Cultured/metabolism ; Tumor Cells, Cultured/transplantation ; Tumor Necrosis Factor-alpha/pharmacology ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factors ; bcl-X Protein

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

CA 75517 United States CA NCI NIH HHS; CA73675 United States CA NCI NIH HHS; CA78778 United States CA NCI NIH HHS

0 (BCL2L1 protein, human)
0 (Bcl2l1 protein, mouse)
0 (Endothelial Growth Factors)
0 (I-kappa B Proteins)
0 (Intercellular Signaling Peptides and Proteins)
0 (Interleukin-8)
0 (Lymphokines)
0 (NF-kappa B)
0 (NFKBIA protein, human)
0 (Neoplasm Proteins)
0 (Nfkbia protein, mouse)
0 (Proto-Oncogene Proteins c-bcl-2)
0 (Recombinant Fusion Proteins)
0 (Tumor Necrosis Factor-alpha)
0 (Vascular Endothelial Growth Factor A)
0 (Vascular Endothelial Growth Factors)
0 (bcl-X Protein)
139874-52-5 (NF-KappaB Inhibitor alpha)
EC 1.13.12.- (Luciferases)

Date Created: 20030306 Date Completed: 20030403 Latest Revision: 20161124

20231215

10.1038/sj.onc.1206323

12618762