Mechanism of action of potato carboxypeptidase inhibitor (PCI) as an EGF blocker

• Published in: Cancer letters 2005-08, Vol.226 (2), p.169-184
• Main Authors: Sitjà-Arnau, Marta, Molina, Miguel A., Blanco-Aparicio, Carmen, Ferrer-Soler, Laura, Lorenzo, Julia, Avilés, Francesc X., Querol, Enrique, Llorens, Rafael de
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Cell Proliferation - drug effects; Colleges & universities; EGF; EGF antagonist; EGFR; Enzyme Activation - drug effects; Epidermal growth factor; Epidermal Growth Factor - antagonists & inhibitors; Epidermal Growth Factor - drug effects; ErbB-2; Female; Humans; Insulin; Kinases; Ligands; Molecular weight; PCI; Phosphorylation; Plant Proteins - pharmacology; Protease Inhibitors - pharmacology; Proteins; Receptor, Epidermal Growth Factor - drug effects; Recombinant Proteins - drug effects; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Rodents; Signal transduction; Signal Transduction - drug effects; Solanum tuberosum; TGF-α; Transforming Growth Factor alpha - antagonists & inhibitors; Transforming Growth Factor alpha - drug effects; Tumors
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2005.01.025

The epidermal growth factor receptor (EGFR) signal transduction pathway plays a prominent role in the development of carcinomas, and is an interesting target for antitumoral therapy. We have previously described how potato carboxypeptidase inhibitor (PCI), a 39-amino acid protease inhibitor with a T-Knot motif, binds to EGFR receptor and inhibits the activation of receptor protein tyrosine kinase. In this paper it is shown that PCI interferes with EGFR activation through inhibition of receptor dimerization and receptor transphosphorylation induced by epidermal growth factor (EGF) and by transforming growth factor alpha (TGF-α). Moreover, PCI blocks the formation and activation of ErbB1/ErbB-2 heterodimers that have a prominent role in carcinoma development. As a result of these effects, PCI interferes in the EGFR signal transduction pathway by reversing the effects of EGF on the growth of two tumoral cell lines, A431 and MDA-MB-453, and promotes EGFR down-regulation. These results show that PCI acts as an EGF/TGF-α antagonist, which suggests its therapeutic potential in the treatment of carcinomas.