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Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA

Oncogene volume 18, pages 4554–4563 (1999)Cite this article

Abstract

The Rel/NF-κB transcription factors regulate the expression of many genes. The activity of RelA, a member of the Rel/NF-κB 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-κB binding site that directly mediates the induction of uPA expression by RelA. Expression of a dominant-negative IκBα mutant inhibits κB site-dependent transcriptional activation of a uPA promoter-CAT reporter gene. Treating the pancreatic tumor cell lines with the known NF-κB 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.

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Acknowledgements

This work was supported in part by a MD Anderson Cancer Center PRS grant and NIH grant (CA73675-01A1) to PJ Chiao, and by NIH grant (CA71836-01) to DB Evans. We thank Dr Marsha L Frazier for providing us with pancreatic cancer cell lines, Dr Dan Van Antwerp and Dr Inder M Verma for providing pIκBαM plasmid, Dr Douglas Boyd for providing uPA promoter, Di Shen and Lillie Larry for technical assistance, and Leslie Wildrick and Pat Thomas for editorial assistance.

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Authors and Affiliations

  1. Department of Surgical Oncology, The University of Texas MD Andersen Cancer Center, Houston, TX 77030, Texas, USA

    Weixin Wang, Douglas B Evans & Paul J Chiao

  2. Department of Gastrointestinal Medical Oncology and Digestive Diseases, The University of Texas MD Andersen Cancer Center, Houston, TX 77030, Texas, USA

    James L Abbruzzese

  3. Department of Tumor Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, Texas, USA

    Paul J Chiao

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Wang, W., Abbruzzese, J., Evans, D. et al. Overexpression of urokinase-type plasminogen activator in pancreatic adenocarcinoma is regulated by constitutively activated RelA. Oncogene 18, 4554–4563 (1999). https://doi.org/10.1038/sj.onc.1202833

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