title: RON Nuclear Translocation under Hypoxia Potentiates Chemoresistance to DNA Double-Strand Break-Inducing Anticancer Drugs.
abstract: Tumor hypoxia is associated with radioresistance, chemoresistance, and metastasis, which eventually lead to cancer progression and a poor patient prognosis. RON [also known as macrophage-stimulating protein receptor (MST1R)] belongs to the c-MET [also known as hepatocyte growth factor receptor (HGFR)] receptor tyrosine kinase (RTK) superfamily. To identify the interaction partners of RON nuclear translocation in response to hypoxia, the nuclear extract of TSGH8301 bladder cancer cells was immunoprecipitated for tandem mass profiling analysis. Nuclear RON interacted with adenosine triphosphate (ATP)-dependent DNA helicase 2 (Ku70) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to activate nonhomologous end joining (NHEJ) DNA repair. The interaction was time dependent, extending 3 to 24 hours posthypoxia or until the components had been exposed to the chemotherapeutic drugs doxorubicin and epirubicin. Stable knockdown experiments in vitro suggest the importance of RON for the chemoresistance of cancer cells under hypoxia. In addition, the tyrosine kinase domain of nuclear RON is crucial for interaction with Ku70 under hypoxia. J82 cells transfected with RON showed a survival advantage in the presence of epirubicin and hypoxia. This suggests that nuclear RON activates NHEJ repair by interacting with Ku70/DNA-PKcs and inhibiting RON activity to increase cancer cell chemosensitivity. Mol Cancer Ther; 15(2); 276-86. ©2016 AACR.
authors.affiliation: Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Chang
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ting-Chia
authors.initials: TC
authors.lastname: Chang
authors.affiliation: Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Wen-Ya
authors.initials: WY
authors.lastname: Huang
authors.affiliation: Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chung-Ta
authors.initials: CT
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.affiliation: Department of Urology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yuh-Shyan
authors.initials: YS
authors.lastname: Tsai
authors.affiliation: Department of Urology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Tzong-Shin
authors.initials: TS
authors.lastname: Tzai
authors.affiliation: Department of Chemistry, College of Sciences, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. chownh@mail.ncku.edu.tw.
authors.forename: Nan-Haw
authors.initials: NH
authors.lastname: Chow
mesh_terms: D034961:Antigens, Nuclear / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D059766:DNA End-Joining Repair; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015251:Epirubicin / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D000072200:Ku Autoantigen; D009687:Nuclear Proteins / Q000378:metabolism*; D021381:Protein Transport; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D015251:Epirubicin; D004317:Doxorubicin; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D000072200:Ku Autoantigen