Faculty Collaboration Database

Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA. Oncogene 1999 Aug 12;18(32):4554-63

Date

09/01/1999

Pubmed ID

10467400

DOI

10.1038/sj.onc.1202833

Scopus ID

2-s2.0-0033549875 (requires institutional sign-in at Scopus site)   153 Citations

Abstract

The Rel/NF-kappaB transcription factors regulate the expression of many genes. The activity of RelA, a member of the Rel/NF-kappaB transcription factor family, is constitutively activated in the majority of pancreatic adenocarcinomas and cell lines. We report that the urokinase-type plasminogen activator (uPA), one of the critical proteases involved in tumor invasion and metastasis, is overexpressed in pancreatic tumor cells and its overexpression is induced by constitutive RelA activity. The uPA promoter contains an NF-kappaB binding site that directly mediates the induction of uPA expression by RelA. Expression of a dominant-negative IkappaBalpha mutant inhibits kappaB site-dependent transcriptional activation of a uPA promoter-CAT reporter gene. Treating the pancreatic tumor cell lines with the known NF-kappaB inhibitors, dexamethasone and n-tosylphenyalanine chloromethyl ketone (TPCK), abolishes constitutive RelA activity and uPA overexpression. These results show that uPA is one of the downstream target genes induced by constitutively activated RelA in human pancreatic tumor cells, and suggests that constitutive RelA activity may play a critical role in tumor invasion and metastasis. Inhibition of constitutive RelA in pancreatic tumor cells may reduce their invasive and metastatic potential.

Author List

Wang W, Abbruzzese JL, Evans DB, 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
Cell Adhesion
Dexamethasone
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
NF-kappa B
Pancreatic Neoplasms
Tosylphenylalanyl Chloromethyl Ketone
Transcription Factor RelA
Transcription, Genetic
Tumor Cells, Cultured
Urokinase-Type Plasminogen Activator