Genistein sensitizes glioblastoma cells to carbon ions via inhibiting DNA-PKcs phosphorylation and subsequently repressing NHEJ and delaying HR repair pathways. Issue 1 (October 2018)

• Record Type: Journal Article
• Authors: Liu, Xiongxiong; Li, Ping; Hirayama, Ryoichi; Niu, Yuzhen; Liu, Xinguo; Chen, Weiqiang; Jin, Xiaodong; Zhang, Pengcheng; Ye, Fei; Zhao, Ting; Liu, Bingtao; Li, Qiang
• Is Part Of: Radiotherapy and oncology. Volume 129:Issue 1(2018)
• Page Start: 84
• Page End: 94
• Publication Date: 2018-10
• Subjects: Genistein -- DNA-PKcs -- Carbon ion radiotherapy -- Radiosensitization -- DSB repair; Oncology -- Periodicals; Radiotherapy -- Periodicals; Tumors -- Periodicals; Medical Oncology -- Periodicals; Neoplasms -- radiotherapy -- Periodicals; Radiotherapy -- Periodicals; Radiothérapie -- Périodiques; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9940642
• DOI: 10.1016/j.radonc.2018.04.005
• Languages: English
• ISSNs: 0167-8140

Abstract

Abstract: Background and purpose: Previously, we found genistein could sensitize cancer cells to low linear energy transfer (LET) X-rays via inhibiting DNA-PKcs activities. Especially, high-LET heavy ion produces more DNA double strand breaks (DSBs) than low-LET radiation. Thus, the study was designed to investigate the detailed molecular mechanisms of genistein on sensitizing cancer cells to heavy ions. Materials and methods: Human glioblastoma (GBM) cell lines with or without genistein pre-treatment were irradiated with high-LET carbon ions. Cell survival was determined with colony formation assay. DNA DSBs were evaluated by means of detecting γ-H2AX foci and immuno-blotting DSB repair proteins, cell apoptosis was detected using Annexin V and PI staining. The interaction of genistein with DNA-PKcs activation site was estimated by molecular docking in the autodock software. Results: Genistein sensitized DNA-PKcs proficient GBM cells to high-LET carbon ions via delaying the clearance of γ-H2AX foci. Genistein was physically bound to DNA-PKcs and functionally inhibited the phosphorylation of DNA-PKcs. Consequently, the non-homologous end joining (NHEJ) repair of DSBs was inhibited and the homologous recombination (HR) repair was delayed by genistein, thereby leading to an increase in apoptosis in DNA-PKcs proficient GBM cells after irradiation. Conclusion: Our study demonstrated that genistein holds promise as a radiosensitizer for enhancing the efficacy of carbon ion radiotherapy against DNA-PKcs proficient GBM via inhibiting DNA-PKcs phosphorylation and subsequently repressing NHEJ and delaying HR repair pathways.