title: FGFR1 Induces Glioblastoma Radioresistance through the PLCγ/Hif1α Pathway.
abstract: FGF2 signaling in glioblastoma induces resistance to radiotherapy, so targeting FGF2/FGFR pathways might offer a rational strategy for tumor radiosensitization. To investigate this possibility, we evaluated a specific role for FGFR1 in glioblastoma radioresistance as modeled by U87 and LN18 glioblastomas in mouse xenograft models. Silencing FGFR1 decreased radioresistance in a manner associated with radiation-induced centrosome overduplication and mitotic cell death. Inhibiting PLCγ (PLCG1), a downstream effector signaling molecule for FGFR1, was sufficient to produce similar effects, arguing that PLCγ is an essential mediator of FGFR1-induced radioresistance. FGFR1 silencing also reduced expression of HIF1α, which in addition to its roles in hypoxic responses exerts an independent effect on radioresistance. Finally, FGFR1 silencing delayed the growth of irradiated tumor xenografts, in a manner that was associated with reduced HIF1α levels but not blood vessel alterations. Taken together, our results offer a preclinical proof of concept that FGFR1 targeting can degrade radioresistance in glioblastoma, a widespread problem in this tumor, prompting clinical investigations of the use of FGFR1 inhibitors for radiosensitization. Cancer Res; 76(10); 3036-44. ©2016 AACR.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037/Université Toulouse III Paul Sabatier, Cancer Research Center of Toulouse (CRCT), Team 11, Toulouse, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gouazé-Andersson
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037/Université Toulouse III Paul Sabatier, Cancer Research Center of Toulouse (CRCT), Team 11, Toulouse, France. Institut Claudius Regaud, IUCT-O, Toulouse, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Delmas
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037/Université Toulouse III Paul Sabatier, Cancer Research Center of Toulouse (CRCT), Team 11, Toulouse, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Taurand
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037/Université Toulouse III Paul Sabatier, Cancer Research Center of Toulouse (CRCT), Team 11, Toulouse, France. Institut Claudius Regaud, IUCT-O, Toulouse, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Martinez-Gala
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037/Université Toulouse III Paul Sabatier, Cancer Research Center of Toulouse (CRCT), Team 11, Toulouse, France.
authors.forename: Solène
authors.initials: S
authors.lastname: Evrard
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037/Université Toulouse III Paul Sabatier, Cancer Research Center of Toulouse (CRCT), Team 11, Toulouse, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Mazoyer
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037/Université Toulouse III Paul Sabatier, Cancer Research Center of Toulouse (CRCT), Team 11, Toulouse, France. Institut Claudius Regaud, IUCT-O, Toulouse, France. moyal.elizabeth@iuct-oncopole.fr toulas.christine@iuct-oncopole.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Toulas
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037/Université Toulouse III Paul Sabatier, Cancer Research Center of Toulouse (CRCT), Team 11, Toulouse, France. Institut Claudius Regaud, IUCT-O, Toulouse, France. moyal.elizabeth@iuct-oncopole.fr toulas.christine@iuct-oncopole.fr.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cohen-Jonathan-Moyal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D049109:Cell Proliferation / Q000528:radiation effects; D018385:Centrosome / Q000528:radiation effects; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000528:radiation effects; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011836:Radiation Tolerance; D060888:Real-Time Polymerase Chain Reaction; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051966:Phospholipase C gamma