title: Growth Differentiation Factor-15 (GDF-15) is a potential marker of radiation response and radiation sensitivity.
abstract: We have investigated the importance of GDF-15 (secreted cytokine belonging to the TGF-β superfamily) in low and high dose radiation-induced cellular responses. A telomerase immortalized human fibroblast cell line (F11hT) was used in the experiments. A lentiviral system encoding small hairpin RNAs (shRNA) was used to establish GDF-15 silenced cells. Secreted GDF-15 levels were measured in culture medium by ELISA. Cell cycle analysis was performed by flow cytometry. The experiments demonstrated that in irradiated human fibroblasts GDF-15 expression increased with dose starting from 100mGy. Elevated GDF-15 expression was not detected in bystander cells. The potential role of GDF-15 in radiation response was investigated by silencing GDF-15 in immortalized human fibroblasts with five different shRNA encoded in lentiviral vectors. Cell lines with considerably reduced GDF-15 levels presented increased radiation sensitivity, while a cell line with elevated GDF-15 was more radiation resistant than wild type cells. We have investigated how the reduced GDF-15 levels alter the response of several known radiation inducible genes. In F11hT-shGDF-15 cells the basal expression level of CDKN1A was unaltered relative to F11hT cells, while GADD45A and TGF-β1 mRNA levels were slightly higher, and TP53INP1 was considerably reduced. The radiation-induced expression of TP53INP1 was lower in the silenced than in wild type fibroblast cells. Cell cycle analysis indicated that radiation-induced early G2/M arrest was abrogated in GDF-15 silenced cells. Moreover, radiation-induced bystander effect was less pronounced in GDF-15 silenced fibroblasts. In conclusion, the results suggest that GDF-15 works as a radiation inducible radiation resistance increasing factor in normal human fibroblast cells, acts by regulating the radiation-induced transcription of several genes and might serve as a radiation-induced early biomarker in exposed cells.
authors.affiliation: Division of Molecular Radiobiology and Biodosimetry, F. Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Anna 5., Budapest, Hungary.
authors.forename: Nikolett
authors.initials: N
authors.lastname: Sándor
authors.affiliation: Division of Molecular Radiobiology and Biodosimetry, F. Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Anna 5., Budapest, Hungary.
authors.forename: Boglárka
authors.initials: B
authors.lastname: Schilling-Tóth
authors.affiliation: Division of Molecular Radiobiology and Biodosimetry, F. Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Anna 5., Budapest, Hungary.
authors.forename: Enikő
authors.initials: E
authors.lastname: Kis
authors.affiliation: Division of Cellular and Immune-radiobiology, F. Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Anna 5., Budapest, Hungary.
authors.forename: Anett
authors.initials: A
authors.lastname: Benedek
authors.affiliation: Division of Cellular and Immune-radiobiology, F. Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Anna 5., Budapest, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Lumniczky
authors.affiliation: Division of Molecular Radiobiology and Biodosimetry, F. Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Anna 5., Budapest, Hungary. Electronic address: safrany.geza@osski.hu.
authors.forename: Géza
authors.initials: G
authors.lastname: Sáfrány
authors.affiliation: Division of Molecular Radiobiology and Biodosimetry, F. Joliot-Curie National Research Institute for Radiobiology and Radiohygiene, Anna 5., Budapest, Hungary; Department of Morphology and Physiology, College of Health Care, Semmelweis University, Budapest, Hungary.
authors.forename: Hargita
authors.initials: H
authors.lastname: Hegyesi
mesh_terms: D002453:Cell Cycle / Q000528:radiation effects; D002460:Cell Line; D002648:Child; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects*; D005786:Gene Expression Regulation / Q000528:radiation effects; D020868:Gene Silencing; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D034741:RNA, Small Interfering / Q000378:metabolism; D011836:Radiation Tolerance
chemical_list: C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D034741:RNA, Small Interfering
keywords: Cell cycle; GDF-15 gene; Human fibroblast; RNA interference; Radiation targets; Radiosensitivity