Abstract
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.
Highlights
Fibroblast growth factor-8 (FGF8), originally cloned from an androgen-dependent mouse mammary carcinoma cell line, belongs to the angiogenic FGF family [1, 2]
The activity was lost when the Pro3 residue was replaced in Ac-ARACANH2 and Ac-ARGCA-NH2 peptides or when the Cys4 residue was replaced in Ac-ARPSA-NH2, Ac-ARPMANH2, and Ac-ARPVA-NH2 peptides, underlying the role of the RPC amino acid sequence in ARPCA/ Fibroblast growth factor-8b (FGF8b) interaction
FGF8b affects epithelial/stromal compartments of steroid hormone-regulated tumors by exerting an autocrine activity on cancer cells and a paracrine pro-angiogenic function that may contribute to tumor progression [4,5,6, 8]
Summary
Fibroblast growth factor-8 (FGF8), originally cloned from an androgen-dependent mouse mammary carcinoma cell line, belongs to the angiogenic FGF family [1, 2]. We demonstrate the capacity of ARPCA to bind FGF8b, inhibiting its angiogenic activity in vitro and in vivo. ARPCA inhibits HUVEC proliferation in response to FGF8b with an IC50 value equal to ~30 μM whereas no significant effect was observed when cells were treated with ARPVA at concentrations as high as 300 μM (Figure 2B).
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