Abstract
FGFRs are considered essential targets for cancer therapy. We previously reported that msFGFR2c, a Ser252Trp mutant soluble ectodomain of FGFR2IIIc, inhibited tumor growth by blocking FGF signaling pathway. However, the underlying molecular mechanism is still obscure. In this study, we reported that msFGFR2c but not wild-type soluble ectodomain of FGFR2IIIc (wsFGFR2c) could selectively bind to c subtype of FGFRs in the presence of FGF-2. Thermodynamic analysis demonstrated that msFGFR2c bound to wsFGFR2c in the presence of FGF-2 with a K value of 6.61 × 105 M−1. Molecular dynamics simulations revealed that the mutated residue Trp252 of msFGFR2c preferred a π-π interaction with His254 of wsFGFR2c. Concomitantly, Arg255 of msFGFR2c and Glu250 of wsFGFR2c adjusted their conformations and formed three H-bonds. These two interactions therefore stabilized the final structure of wsFGFR2c and msFGFR2c heterocomplex. In FGFR2IIIc-positive/high FGF-2-secreted BT-549 cells, msFGFR2c significantly inhibited the proliferation and induced apoptosis by the blockage of FGF-2-activated FGFRs phosphorylation, also the growth and angiogenesis of its xenograft tumors implanted in chick embryo chorioallantoic membrane model. While weaker the above inhibitory effects of msFGFR2c were observed on FGFR2IIIc-negative/low FGF-2-secreted MCF-7 and MDA-MB-231 cell lines in vitro and in vivo. Moreover, msFGFR2c significantly inhibited the proliferation of FGFR1IIIc-positive NCI-H1299 lung cancer cells by the suppression of FGF-2-induced FGFR1 activation and suppressed the growth of NCI-H1299 transplanted tumors in nude mice. In sum, msFGFR2c is a potential anti-tumor agent targeting FGFR2c/FGFR1c-positive tumor cells. These findings also provide a molecular basis for msFGFR2c to disrupt the activation of FGF signaling.
Highlights
It is well known that receptor tyrosine kinases (RTKs) play important roles in the development and progression of human cancers [1]
Confocal microscopy analysis showed that msFGFR2c rather than wsFGFR2c co-localized with FGFRs in the presence of FGF-2 (Figure 2), which was consistent with the co-immunoprecipitation analysis
Since receptor dimerization depends on the close of membrane domains, there is a paradox that ectodomain of receptors dimerization needs the help of membrane domains [29, 30]
Summary
It is well known that receptor tyrosine kinases (RTKs) play important roles in the development and progression of human cancers [1]. Several strategies to block RTK signal pathways have been developed, such as neutralizing antibodies targeting ligands or receptors, small molecular RTK inhibitors (TKIs) and so on [2, 3]. Soluble receptors may have some advantages as antitumor agents since the ability of blocking RTK signaling pathways in a network type by trapping kinds of ligands. We further observed that the inhibitory effects of msFGFR2c was associated with the concentrations of ligand (FGF-2) and with the endogenous expression of FGFRs in the different types of cancer cells. We reported that msFGFR2c but not wsFGFR2c (wild-type ectodomain of FGFR2c) could selectively bind to c subtype of FGFRs in the presence of FGF-2. The results will be definitely a peek into the future application of msFGFR2c in cancer targeting therapy
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