title: Inhibition of constitutive NF-kappa B activity by I kappa B alpha M suppresses tumorigenesis.
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.
authors.affiliation: Department of Surgical Oncology, The University of Texas, Houston 77030, USA.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Fujioka
authors.forename: Guido M
authors.initials: GM
authors.lastname: Sclabas
authors.forename: Christian
authors.initials: C
authors.lastname: Schmidt
authors.forename: Jiangong
authors.initials: J
authors.lastname: Niu
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Frederick
authors.forename: Qiang G
authors.initials: QG
authors.lastname: Dong
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Evans
authors.forename: Cheryl
authors.initials: C
authors.lastname: Baker
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Chiao
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D019254:Genes, bcl-2; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008222:Lymphokines / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000517:prevention & control*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051020:bcl-X Protein
chemical_list: C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D016228:Endothelial Growth Factors; D020672:I-kappa B Proteins; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D008222:Lymphokines; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; C000606205:Nfkbia protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051020:bcl-X Protein; D000072000:NF-KappaB Inhibitor alpha; D008156:Luciferases