Fibroblast Growth Factor/FGF Receptor 1 (FGF2/FGFR1) system regulates the growth and metastasis of different cancers. Inhibition of this signaling pathway is an attractive target for cancer therapy. Here, we aimed to reproduce the 118–126 fragment of FGF2 to interfere with the FGF2–FGFR1 interaction. To determine whether the loop structure affects the function of this fragment, we compared cyclic (disulfide-bonded) and linear peptide variants. The cyclic peptide (referred to as BGF1) effectively inhibited the FGF2-induced proliferation of HUVECs, 4T1 mammary carcinoma, U87 glioblastoma, and SKOV3 ovarian carcinoma cells. It led to apoptosis induction in HUVECs, whereas the linear peptide (referred to as BGF2) was ineffective. In a murine 4T1 tumor model, BGF1 inhibited tumor growth more effectively than Avastin and increased animals’ survival without causing weight loss, but the linear peptide BGF2 had no significant anti-tumor effects. According to immunohistochemical studies, the anti-tumor properties of BGF1 were associated with suppression of tumor cell proliferation (Ki-67 expression), angiogenesis (CD31 expression), and apoptosis induction (as was shown by increased p53 expression and TUNEL staining and decreased Bcl-2 expression). The potential of BGF1 to suppress tumor invasion was indicated by quantitative analysis of the metastasis-related proteins, including FGFR1, pFGFR1, NF-κB, p-NF-κB, MMP-9, E-cadherin, N-cadherin, and Vimentin, and supported by small animal positron emission tomography (PET) used 18Fluorodeoxyglucose (18F-FDG). These results demonstrate that the functional properties of the 118–126 region of FGF2 depend on the loop structure and the peptide derived from this fragment encourages further preclinical investigations.
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The substrate and inhibitor binding pocket within the alternative oxidase (AOX). This pocket represents a novel therapeutic and agrochemical target whereas expression of the protein a possible rescue mechanism for the treatment of a number of mitochondrial diseases and sepsis. Read more from Anthony L. Moore and colleagues in Targeting the alternative oxidase (AOX) for human health and food security, a pharmaceutical and agrochemical target or a rescue mechanism? on pages 1287 to 1309.
Anti-tumor and anti-metastatic activity of the FGF2 118–126 fragment dependent on the loop structure
Hossein Allahmoradi, S. Mohsen Asghari, Atieh Ahmadi, Elham Assareh, Mahboobeh Nazari; Anti-tumor and anti-metastatic activity of the FGF2 118–126 fragment dependent on the loop structure. Biochem J 30 June 2022; 479 (12): 1285–1302. doi: https://doi.org/10.1042/BCJ20210830
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