RRC ID 44786
Author Nakayama F, Umeda S, Yasuda T, Fujita M, Asada M, Meineke V, Imamura T, Imai T.
Title Cellular internalization of fibroblast growth factor-12 exerts radioprotective effects on intestinal radiation damage independently of FGFR signaling.
Journal Int. J. Radiat. Oncol. Biol. Phys.
Abstract PURPOSE:Several fibroblast growth factors (FGFs) were shown to inhibit radiation-induced tissue damage through FGF receptor (FGFR) signaling; however, this signaling was also found to be involved in the pathogenesis of several malignant tumors. In contrast, FGF12 cannot activate any FGFRs. Instead, FGF12 can be internalized readily into cells using 2 cell-penetrating peptide domains (CPP-M, CPP-C). Therefore, this study focused on clarifying the role of FGF12 internalization in protection against radiation-induced intestinal injury.
METHODS AND MATERIALS:Each FGF or peptide was administered intraperitoneally to BALB/c mice in the absence of heparin 24 hours before or after total body irradiation with γ rays at 9 to 12 Gy. Several radioprotective effects were examined in the jejunum.
RESULTS:Administration of FGF12 after radiation exposure was as effective as pretreatment in significantly promoting intestinal regeneration, proliferation of crypt cells, and epithelial differentiation. Two domains, comprising amino acid residues 80 to 109 and 140 to 169 of FGF12B, were identified as being responsible for the radioprotective activity, so that deletion of both domains from FGF12B resulted in a reduction in activity. Interestingly, these regions included the CPP-M and CPP-C domains, respectively; however, CPP-C by itself did not show an antiapoptotic effect. In addition, FGF1, prototypic FGF, possesses a domain corresponding to CPP-M, whereas it lacks CPP-C, so the fusion of FGF1 with CPP-C (FGF1/CPP-C) enhanced cellular internalization and increased radioprotective activity. However, FGF1/CPP-C reduced in vitro mitogenic activity through FGFRs compared with FGF1, implying that FGFR signaling might not be essential for promoting the radioprotective effect of FGF1/CPP-C. In addition, internalized FGF12 suppressed the activation of p38α after irradiation, resulting in reduced radiation-induced apoptosis.
CONCLUSIONS:These findings indicate that FGF12 can protect the intestine against radiation-induced injury through its internalization, independently of FGFRs, suggesting that cellular uptake of FGF12 is an alternative signaling pathway useful for cancer radiation therapy.
Volume 88(2)
Pages 377-84
Published 2014-2-1
DOI 10.1016/j.ijrobp.2013.10.035
PII S0360-3016(13)03282-3
PMID 24315567
MeSH Amino Acids / physiology Animals Cell Proliferation / drug effects Fibroblast Growth Factors / chemistry Fibroblast Growth Factors / metabolism* Jejunum / metabolism Jejunum / physiology Jejunum / radiation effects* Male Mice Mice, Inbred BALB C Radiation Injuries, Experimental / physiopathology Radiation Injuries, Experimental / prevention & control* Radiation Tolerance / physiology* Receptors, Fibroblast Growth Factor / metabolism* Regeneration / drug effects Regeneration / physiology Whole-Body Irradiation
IF 6.203
Times Cited 3
Human and Animal Cells