A peptide derived from the nonreceptor binding region of urokinase plasminogen activator (uPa) inhibits tumor progression and angiogenesis and induces tumor cell death in vivo

Yongjing Guo, Abd Al-Roof Higazi, Ani Arakelian, Bruce S. Sachais, Douglas Cines, Ronald H. Goldfarb, Terence R. Jones, H. Kwaan, Andrew P. Mazar, Shafaat A. Rabbani*

*Corresponding author for this work

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

Urokinase plasminogen activator (uPA) plays an important role in the progression of several malignancies including breast cancer. We have identified a noncompetitive antagonist of the uPA-uPAR interaction derived from a nonreceptor binding region of uPA (amino acids 136-143). This 8-mer capped peptide (A6) inhibited breast cancer cell invasion and endothelial cell migration in a dose-dependent manner in vitro without altering cell doubling time. Intraperitoneal administration of A6 resulted in a significant inhibition of tumor growth and suppressed the development of lymph node metastases in several models of breast cancer cell growth and metastasis. Large areas of tumor necrosis and extensive positive staining by TUNEL were observed on histological and immunohistochemical analysis of experimental tumor sections from Å6-treated animals. Å6 treatment also resulted in a decrease in factor VIII-positive tumor microvessel hot-spots. These results identify a new epitope in uPA that is involved in the uPA-uPAR interaction and indicate that an antagonist based on this epitope is able to inhibit tumor progression by modulating the tumor microenvironment in the absence of direct cytotoxic effects in vivo.

Original languageEnglish (US)
Pages (from-to)1400-1410
Number of pages11
JournalFASEB Journal
Volume14
Issue number10
DOIs
StatePublished - 2000

Keywords

  • Apoptosis
  • Breast cancer
  • Endothelial cell
  • Tumor necrosis

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Guo, Y., Al-Roof Higazi, A., Arakelian, A., Sachais, B. S., Cines, D., Goldfarb, R. H., Jones, T. R., Kwaan, H., Mazar, A. P., & Rabbani, S. A. (2000). A peptide derived from the nonreceptor binding region of urokinase plasminogen activator (uPa) inhibits tumor progression and angiogenesis and induces tumor cell death in vivo. FASEB Journal, 14(10), 1400-1410. https://doi.org/10.1096/fasebj.14.10.1400