ATR-dependent radiation-induced γH2AX foci in bystander primary human astrocytes and glioma cells

被引:157
作者
Burdak-Rothkamm, S.
Short, S. C.
Folkard, M.
Rothkamm, K.
Prise, K. M.
机构
[1] Mt Vernon Hosp, Gray Canc Inst, Northwood HA6 2JR, Middx, England
[2] Univ Oxford, Gray Canc Inst, Oxford OX1 2JD, England
关键词
ATR; gamma H2AX; DNA damage; charged particle irradiation; targeted irradiation; bystander signalling;
D O I
10.1038/sj.onc.1209863
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 de. ne 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 gamma H2AX foci in neighbouring non-targeted bystander cells up to 48 h after irradiation. gamma H2AX bystander foci were also observed in co-cultures targeting either NHA or T98G cells and in medium transfer experiments. Dimethyl sulphoxide, Filipin and antitransforming growth factor (TGF)-beta 1 could suppress gamma H2AX 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 gamma H2AX 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 gamma H2AX 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.
引用
收藏
页码:993 / 1002
页数:10
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