title: The radioprotective effect of the 24 kDa FGF-2 isoform in HeLa cells is related to an increased expression and activity of the DNA dependent protein kinase (DNA-PK) catalytic subunit.
abstract: We previously reported that overexpression of the 24 kDa basic fibroblast factor (or FGF-2) isoform provides protection from the cytotoxic effect of ionizing radiation (IR). DNA double-strand breaks (DSB), the IR-induced lethal lesions, are mainly repaired in human cells by non-homologous end joining system (NHEJ). NHEJ reaction is dependent on the DNA-PK holoenzyme (composed of a regulatory sub-unit, Ku, and a catalytic sub-unit, DNA-PKcs) that assembles at sites of DNA damage. We demonstrated here that the activity of DNA-PK was increased by twofold in two independent radioresistant cell lines, HeLa 3A and CAPAN A3, over expressing the 24 kDa FGF-2. This increase was associated with an overexpression of the DNA-PKcs without modification of Ku expression or activity. This overexpression was due to an up-regulation of the DNA-PKcs gene transcription by the 24 kDa FGF-2 isoform. Finally, HeLa 3A cells exhibited the hallmarks of phenotypic changes associated with the overexpression of an active DNA-PKcs. Indeed, a faster repair rate of DSB and sensitization to IR by wortmannin was observed in these cells. Our results represent the characterization of a new mechanism of control of DNA repair and radioresistance in human tumor cells dependent on the overproduction of the 24 kDa FGF-2 isoform.
authors.affiliation: Oncologie Cellulaire et Moléculaire, INSERM U563, Département d'Innovation thérapeutique et Oncologie Moléculaire, Centre de Lutte Contre le Cancer Claudius Regaud, 20-24 rue du Pont St Pierre, 31052 Toulouse Cedex France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ader
authors.forename: Catherine
authors.initials: C
authors.lastname: Muller
authors.forename: Jacques
authors.initials: J
authors.lastname: Bonnet
authors.forename: Gilles
authors.initials: G
authors.lastname: Favre
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cohen-Jonathan
authors.forename: Bernard
authors.initials: B
authors.lastname: Salles
authors.forename: Christine
authors.initials: C
authors.lastname: Toulas
mesh_terms: D000730:Androstadienes / Q000378:metabolism / Q000494:pharmacology*; D034961:Antigens, Nuclear; D015153:Blotting, Western; D004249:DNA Damage / Q000528:radiation effects*; D004265:DNA Helicases; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D006367:HeLa Cells / Q000378:metabolism / Q000528:radiation effects*; D006801:Humans; D000072200:Ku Autoantigen; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D020033:Protein Isoforms / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D011836:Radiation Tolerance; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011837:Radiation-Protective Agents; D016222:Fibroblast Growth Factor 2; D012313:RNA; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D004265:DNA Helicases; C106893:XRCC5 protein, human; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; D000077191:Wortmannin