Development of an epidermal growth factor derivative with EGFR blocking activity.
The members of the epidermal growth factor (EGF)/ErbB family are prime targets for cancer therapy. However, the therapeutic efficiency of the existing anti-ErbB agents is limited. Thus, identifying new molecules that inactivate the ErbB receptors through novel strategies is an important goal on cancer research. In this study we have developed a shorter form of human EGF (EGFt) with a truncated C-terminal as a novel EGFR inhibitor. EGFt was designed based on the superimposition of the three-dimensional structures of EGF and the Potato Carboxypeptidase Inhibitor (PCI), an EGFR blocker previously described by our group. The peptide was produced in E. coli with a high yield of the correctly folded peptide. EGFt showed specificity and high affinity for EGFR but induced poor EGFR homodimerization and phosphorylation. Interestingly, EGFt promoted EGFR internalization and translocation to the cell nucleus although it did not stimulate the cell growth. In addition, EGFt competed with EGFR native ligands, inhibiting the proliferation of cancer cells. These data indicate that EGFt may be a potential EGFR blocker for cancer therapy. In addition, the lack of EGFR-mediated growth-stimulatory activity makes EGFt an excellent delivery agent to target toxins to tumours over-expressing EGFR.
Biochemistry and Molecular Biology Unit. Department of Biology, University of Girona, Campus Montilivi, Girona, Catalunya, Spain.
Clara
C
Panosa
Francesc
F
Tebar
Montserrat
M
Ferrer-Batallé
Humphrey
H
Fonge
Masaharu
M
Seno
Raymond M
RM
Reilly
Anna
A
Massaguer
Rafael
R
De Llorens
D019149:Bioreactors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005285:Fermentation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D021381:Protein Transport; D059748:Proteolysis; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology
D008024:Ligands; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors