title: Differential effects of p53 on bystander phenotypes induced by gamma ray and high LET heavy ion radiation.
abstract: High LET particle irradiation has several potential advantages over γ-rays such as p53-independent response. The purpose of this work is to disclose the effect of p53 on the bystander effect induced by different LET irradiations and underlying mechanism. Lymphocyte cells of TK6 (wild type p53) and HMy2.CIR (mutated p53) were exposed to either low or high LET irradiation, then their mitochondrial dysfunction and ROS generation were detected. The micronuclei (MN) induction in HL-7702 hepatocytes co-cultured with irradiated lymphocytes was also measured. It was found that the mitochondrial dysfunction, p66(Shc) activation, and intracellular ROS were enhanced in TK6 but not in HMy2.CIR cells after γ-ray irradiation, but all of them were increased in both cell lines after carbon and iron irradiation. Consistently, the bystander effect of MN formation in HL-7702 cells was only triggered by γ-irradiated TK6 cells but not by γ-irradiated HMy2.CIR cells. But this bystander effect was induced by both lymphocyte cell lines after heavy ion irradiation. PFT-μ, an inhibitor of p53, only partly inhibited ROS generation and bystander effect induced by 30 keV/μm carbon-irradiated TK6 cells but failed to suppress the bystander effect induced by the TK6 cells irradiated with either 70 keV/μm carbon or 180 keV/μm iron. The mitochondrial inhibitors of rotenone and oligomycin eliminated heavy ion induced ROS generation in TK6 and HMy2.CIR cells and hence diminished the bystander effect on HL-7702 cells. These results clearly demonstrate that the bystander effect is p53-dependent for low LET irradiation, but it is p53-independent for high LET irradiation which may be because of p53-independent ROS generation due to mitochondrial dysfunction.
authors.affiliation: Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032, China; Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun 130000, China.
authors.forename: Mingyuan
authors.initials: M
authors.lastname: He
authors.affiliation: Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.affiliation: Research Development and Support Center, National Institute of Radiological Sciences, Inage, Chiba 263-8555, Japan.
authors.forename: Teruaki
authors.initials: T
authors.lastname: Konishi
authors.affiliation: Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032, China.
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Tu
authors.affiliation: Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032, China.
authors.forename: Weili
authors.initials: W
authors.lastname: Liu
authors.affiliation: Research Development and Support Center, National Institute of Radiological Sciences, Inage, Chiba 263-8555, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Shiomi
authors.affiliation: Research Development and Support Center, National Institute of Radiological Sciences, Inage, Chiba 263-8555, Japan.
authors.forename: Alisa
authors.initials: A
authors.lastname: Kobayashi
authors.affiliation: Research Development and Support Center, National Institute of Radiological Sciences, Inage, Chiba 263-8555, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Uchihori
authors.affiliation: Heavy-Ion Radiobiology Research Group, National Institute of Radiological Sciences, Inage, Chiba 263-8555, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Furusawa
authors.affiliation: Department of Radiation Oncology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Tom K
authors.initials: TK
authors.lastname: Hei
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China.
authors.forename: Bingrong
authors.initials: B
authors.lastname: Dang
authors.affiliation: Institute of Radiation Medicine, Fudan University, No. 2094 Xie-Tu Road, Shanghai 200032, China. Electronic address: clshao@shmu.edu.cn.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Shao
keywords: Bystander effect; Irradiation; LET; Mitochondria; ROS; p53