Faculty Collaboration Database

Inhibition of constitutive NF-kappa B activity by I kappa B alpha M suppresses tumorigenesis. Oncogene 2003 Mar 06;22(9):1365-70

Date

03/06/2003

Pubmed ID

12618762

DOI

10.1038/sj.onc.1206323

Scopus ID

2-s2.0-0037422205 (requires institutional sign-in at Scopus site)   152 Citations

Abstract

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.

Author List

Fujioka S, Sclabas GM, Schmidt C, Niu J, Frederick WA, Dong QG, Abbruzzese JL, Evans DB, Baker C, Chiao PJ

Author

Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Animals
Endothelial Growth Factors
Gene Expression Regulation, Neoplastic
Genes, Reporter
Genes, bcl-2
Humans
I-kappa B Proteins
Intercellular Signaling Peptides and Proteins
Interleukin-8
Luciferases
Lymphokines
Mice
Mice, Nude
Mutation
NF-KappaB Inhibitor alpha
NF-kappa B
Neoplasm Proteins
Neoplasm Transplantation
Neovascularization, Pathologic
Pancreatic Neoplasms
Phosphorylation
Promoter Regions, Genetic
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-bcl-2
Recombinant Fusion Proteins
Tumor Cells, Cultured
Tumor Necrosis Factor-alpha
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
bcl-X Protein