POTATO CARBOXYPEPTIDASE INHIBITOR, A T-KNOT PROTEIN, IS AN EPIDERMAL GROWTH-FACTOR ANTAGONIST THAT INHIBITS TUMOR-CELL GROWTH

Epidermal growth factor (EGF) and its receptor (EGFR) are involved in many aspects of the development of carcinomas, including tumor cell gr owth, vascularization, invasiveness, and metastasis. Because EGFR has been found to be overexpressed in many tumors of epithelial origin, it is a potential target for antitumor therapy. Here we report that pota to carboxypeptidase inhibitor (PCI), a 39-amino acid protease inhibito r with three disulfide bridges, is an antagonist of human EGF. It comp eted with EGF for binding to EGFR and inhibited EGFR activation and ce ll proliferation induced by this growth factor. PCI suppressed the gro wth of several human pancreatic adenocarcinoma cell lines, both in vit ro and in nude mice. PCI has a special disulfide scaffold called a T-k not that is also present in several growth factors including EGF and t ransforming growth factor alpha. PCI shows structural similarities wit h these factors, a fact that can explain the antagonistic effect of th e former. This is the first reported example of an antagonistic analog ue of human EGF.