A Novel Serine Protease Target for Prevention of Breast Cancer by a Soy Bean-Derived Inhibitor
Abstract
This project established the interactions of a novel transmembrane, protease, matritpase, with the chemopreventive Bowman Birk Inhibitor (BBI), compared to its cognate, physiological inhibitor HAI-1. We first established the inhibitory interaction between matriptase and HAI- 1, and between matriptase and BBI; we built a 3-D structure of the protease domain of matriptase, based on the homology modeling using the X-ray structure of human thrombin as template. This modeled matriptase structure was used in a structure-based screening of inhibitors. Screening the NCI small compounds database, allowed discovery of bis-benramidines as potent matriptase inhibitors. We also identified natural trypsin inhibitor, SFTI, from sunflower seed, as a potent inhibitor of matriptase. We found that in non-transformed mammary epithelial cells, matriptase can be activated by lipid phosphates; the activated matriptase is then quickly binds to HAI-1, and is shed into media. Thus, engagement of membrane-bound matriptase with HAI-1 leads to its extracellular shedding. in addition, we identified hepatocyte growth factor and pro-uPA as likely physiological protein substrates of matriptase. Finally, we found that breast cancer cells constitutively activate matriptase, but that cells are not modulated in their proliferation or differentiation by matriptase inhibition in vitro, probably due to the lack of relevant matriptase substrates.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2002
- Accession Number
- ADA407435
Entities
People
- Robert B. Dickson
Organizations
- Georgetown University