A long pentraxin-3-derived pentapeptide for the therapy of FGF8b-driven steroid hormone-regulated cancers.
Fibroblast growth factor-8b (FGF8b) affects the epithelial/stromal compartments of steroid hormone-regulated tumors by exerting an autocrine activity on cancer cells and a paracrine pro-angiogenic function, thus contributing to tumor progression. The FGF8b/FGF receptor (FGFR) system may therefore represent a target for the treatment of steroid hormone-regulated tumors. The soluble pattern recognition receptor long pentraxin-3 (PTX3) binds various FGFs, including FGF2 and FGF8b, thus inhibiting the angiogenic and tumorigenic activity of androgen-regulated tumor cells. Nevertheless, the complex/proteinaceous structure of PTX3 hampers its pharmacological exploitation. In this context, the acetylated pentapeptide Ac-ARPCA-NH2 (ARPCA), corresponding to the N-terminal amino acid sequence PTX3(100-104), was identified as a minimal FGF2-binding peptide able to antagonize the biological activity of FGF2. Here, we demonstrate that ARPCA binds FGF8b and inhibits its capacity to form FGFR1-mediated ternary complexes with heparan sulphate proteoglycans. As a FGF8b antagonist, ARPCA inhibits FGFR1 activation and signalling in endothelial cells, hampering the angiogenic activity exerted in vitro and in vivo by FGF8b. Also, ARPCA suppresses the angiogenic and tumorigenic potential of prototypic androgen/FGF8b-dependent Shionogi 115 mammary carcinoma cells and of androgen/FGF8b/FGF2-dependent TRAMP-C2 prostate cancer cells. In conclusion, ARPCA represents a novel FGF8b antagonist with translational implications for the therapy of steroid hormone-regulated tumors.
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Arianna
A
Giacomini
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Sara
S
Matarazzo
NMR Laboratory, Istituto per lo Studio delle Macromolecole, CNR, Milan, Italy.
Katiuscia
K
Pagano
NMR Laboratory, Istituto per lo Studio delle Macromolecole, CNR, Milan, Italy.
Laura
L
Ragona
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Sara
S
Rezzola
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Michela
M
Corsini
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Emanuela
E
Di Salle
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Marco
M
Presta
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Roberto
R
Ronca
D000818:Animals; D002097:C-Reactive Protein / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008958:Models, Molecular; D009376:Neoplasms, Hormone-Dependent / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D000683:Serum Amyloid P-Component / Q000494:pharmacology*; D000099153:Pentraxins
D002097:C-Reactive Protein; D051524:Fibroblast Growth Factor 8; D010446:Peptide Fragments; D000683:Serum Amyloid P-Component; D000099153:Pentraxins
FGF8; angiogenesis; hormone-regulated cancer; pentraxin; peptide