ATR-dependent radiation-induced gamma H2AX foci in bystander primary human astrocytes and glioma cells
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ATR-dependent radiation-induced gamma H2AX foci in bystander primary human astrocytes and glioma cells. / Burdak-Rothkamm, S; Short, S C; Folkard, M; Rothkamm, K; Prise, K M.
in: ONCOGENE, Jahrgang 26, Nr. 7, 15.02.2007, S. 993-1002.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - ATR-dependent radiation-induced gamma H2AX foci in bystander primary human astrocytes and glioma cells
AU - Burdak-Rothkamm, S
AU - Short, S C
AU - Folkard, M
AU - Rothkamm, K
AU - Prise, K M
PY - 2007/2/15
Y1 - 2007/2/15
N2 - Radiotherapy is an important treatment for patients suffering from high-grade malignant gliomas. Non-targeted (bystander) effects may influence these cells' response to radiation and the investigation of these effects may therefore provide new insights into mechanisms of radiosensitivity and responses to radiotherapy as well as define new targets for therapeutic approaches. Normal primary human astrocytes (NHA) and T98G glioma cells were irradiated with helium ions using the Gray Cancer Institute microbeam facility targeting individual cells. Irradiated NHA and T98G glioma cells generated signals that induced gammaH2AX foci in neighbouring non-targeted bystander cells up to 48 h after irradiation. gammaH2AX bystander foci were also observed in co-cultures targeting either NHA or T98G cells and in medium transfer experiments. Dimethyl sulphoxide, Filipin and anti-transforming growth factor (TGF)-beta 1 could suppress gammaH2AX foci in bystander cells, confirming that reactive oxygen species (ROS) and membrane-mediated signals are involved in the bystander signalling pathways. Also, TGF-beta 1 induced gammaH2AX in an ROS-dependent manner similar to bystander foci. ROS and membrane signalling-dependent differences in bystander foci induction between T98G glioma cells and normal human astrocytes have been observed. Inhibition of ataxia telangiectasia mutated (ATM) protein and DNA-PK could not suppress the induction of bystander gammaH2AX foci whereas the mutation of ATM- and rad3-related (ATR) abrogated bystander foci induction. Furthermore, ATR-dependent bystander foci induction was restricted to S-phase cells. These observations may provide additional therapeutic targets for the exploitation of the bystander effect.
AB - Radiotherapy is an important treatment for patients suffering from high-grade malignant gliomas. Non-targeted (bystander) effects may influence these cells' response to radiation and the investigation of these effects may therefore provide new insights into mechanisms of radiosensitivity and responses to radiotherapy as well as define new targets for therapeutic approaches. Normal primary human astrocytes (NHA) and T98G glioma cells were irradiated with helium ions using the Gray Cancer Institute microbeam facility targeting individual cells. Irradiated NHA and T98G glioma cells generated signals that induced gammaH2AX foci in neighbouring non-targeted bystander cells up to 48 h after irradiation. gammaH2AX bystander foci were also observed in co-cultures targeting either NHA or T98G cells and in medium transfer experiments. Dimethyl sulphoxide, Filipin and anti-transforming growth factor (TGF)-beta 1 could suppress gammaH2AX foci in bystander cells, confirming that reactive oxygen species (ROS) and membrane-mediated signals are involved in the bystander signalling pathways. Also, TGF-beta 1 induced gammaH2AX in an ROS-dependent manner similar to bystander foci. ROS and membrane signalling-dependent differences in bystander foci induction between T98G glioma cells and normal human astrocytes have been observed. Inhibition of ataxia telangiectasia mutated (ATM) protein and DNA-PK could not suppress the induction of bystander gammaH2AX foci whereas the mutation of ATM- and rad3-related (ATR) abrogated bystander foci induction. Furthermore, ATR-dependent bystander foci induction was restricted to S-phase cells. These observations may provide additional therapeutic targets for the exploitation of the bystander effect.
KW - Astrocytes/metabolism
KW - Ataxia Telangiectasia Mutated Proteins
KW - Bystander Effect/radiation effects
KW - Cell Cycle Proteins/genetics
KW - Cell Line
KW - Cell Line, Tumor
KW - Coculture Techniques
KW - Glioma/metabolism
KW - Histones/biosynthesis
KW - Humans
KW - Phosphorylation
KW - Protein-Serine-Threonine Kinases/genetics
KW - S Phase/genetics
KW - Signal Transduction/genetics
U2 - 10.1038/sj.onc.1209863
DO - 10.1038/sj.onc.1209863
M3 - SCORING: Journal article
C2 - 16909103
VL - 26
SP - 993
EP - 1002
JO - ONCOGENE
JF - ONCOGENE
SN - 0950-9232
IS - 7
ER -