title: Radiosensitization of metformin in pancreatic cancer cells via abrogating the G2 checkpoint and inhibiting DNA damage repair.
abstract: Recent evidences have demonstrated the potential of metformin as a novel agent for cancer prevention and treatment. Here, we investigated its ability of radiosensitization and the underlying mechanisms in human pancreatic cancer cells. In this study, we found that metformin at 5 mM concentration enhanced the radiosensitivity of MIA PaCa-2 and PANC-1 cells, with sensitization enhancement ratios of 1.39 and 1.27, respectively. Mechanistically, metformin caused abrogation of the G2 checkpoint and increase of mitotic catastrophe, associated with suppression of Wee1 kinase and in turn CDK1 Tyr15 phosphorylation. Furthermore, metformin inhibited both expression and irradiation-induced foci formation of Rad51, a key player in homologous recombination repair, ultimately leading to persistent DNA damage, as reflected by γ-H2AX and 53BP1 signaling. Finally, metformin-mediated AMPK/mTOR/p70S6K was identified as a possible upstream pathway controlling translational regulation of Wee1 and Rad51. Our data suggest that metformin radiosensitizes pancreatic cancer cells in vitro via abrogation of the G2 checkpoint and inhibition of DNA damage repair. However, the in vivo study is needed to further confirm the findings from the in vitro study.
authors: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai 200032, China.
authors: Zheng
authors: Z
authors: Wang
authors: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai 200032, China.
authors: Song-Tao
authors: ST
authors: Lai
authors: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai 200032, China.
authors: Ning-Yi
authors: NY
authors: Ma
authors: Cancer Research Institute, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China.
authors: Yun
authors: Y
authors: Deng
authors: Cancer Research Institute, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China.
authors: Yong
authors: Y
authors: Liu
authors: Cancer Research Institute, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China.
authors: Dong-Ping
authors: DP
authors: Wei
authors: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai 200032, China.
authors: Jian-Dong
authors: JD
authors: Zhao
authors: Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dongan Road, Shanghai 200032, China; Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, 4365 Kangxin Road, Shanghai 201321, China. Electronic address: guoliang.jiang@sphic.org.cn.
authors: Guo-Liang
authors: GL
authors: Jiang
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy*; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011838:Radiation-Sensitizing Agents; D008687:Metformin; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase
keywords: Metformin; Pancreatic cancer; Rad51; Radiosensitizer; Wee1; mTOR