title: Cellular internalization of fibroblast growth factor-12 exerts radioprotective effects on intestinal radiation damage independently of FGFR signaling.
abstract: OBJECTIVE
  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
  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.
authors: Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, Chiba, Japan. Electronic address: f_naka@nirs.go.jp.
authors: Fumiaki
authors: F
authors: Nakayama
authors: Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, Chiba, Japan.
authors: Sachiko
authors: S
authors: Umeda
authors: Radiation Emergency Medicine Research Program, Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Chiba, Japan.
authors: Takeshi
authors: T
authors: Yasuda
authors: Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, Chiba, Japan.
authors: Mayumi
authors: M
authors: Fujita
authors: Signaling Molecules Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan.
authors: Masahiro
authors: M
authors: Asada
authors: Bundeswehr Institute of Radiobiology affiliated to the University of Ulm, Munich, Germany.
authors: Viktor
authors: V
authors: Meineke
authors: Signaling Molecules Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan.
authors: Toru
authors: T
authors: Imamura
authors: Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, Chiba, Japan.
authors: Takashi
authors: T
authors: Imai
mesh_terms: D000596:Amino Acids / Q000502:physiology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000737:chemistry / Q000378:metabolism*; D007583:Jejunum / Q000378:metabolism / Q000502:physiology / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011833:Radiation Injuries, Experimental / Q000503:physiopathology / Q000517:prevention & control*; D011836:Radiation Tolerance / Q000502:physiology*; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D014916:Whole-Body Irradiation
chemical_list: D000596:Amino Acids; C108110:Fgf12 protein, mouse; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors