Mechanism of action of potato carboxypeptidase inhibitor (PCI) as an EGF blocker.
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-alpha). 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-alpha antagonist, which suggests its therapeutic potential in the treatment of carcinomas.
Sitjà-Arnau
Marta
M
Unitat de Bioquímica, Departament de Biologia, Facultat de Ciències, Universitat de Girona, Campus de Montilivi, 17071 Girona, Spain.
Molina
Miguel A
MA
Blanco-Aparicio
Carmen
C
Ferrer-Soler
Laura
L
Lorenzo
Julia
J
Avilés
Francesc X
FX
Querol
Enrique
E
de Llorens
Rafael
R
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors / Q000187:drug effects*; D066246:ErbB Receptors / Q000187:drug effects; D005260:Female; D006801:Humans; D010766:Phosphorylation; D010940:Plant Proteins / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D016211:Transforming Growth Factor alpha / Q000037:antagonists & inhibitors / Q000187:drug effects
D010940:Plant Proteins; D011480:Protease Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D066246:ErbB Receptors