title: The expression of DNA damage checkpoint proteins and prognostic implication in metastatic brain tumors.
abstract: The most important therapeutic tool in brain metastasis is radiation therapy. However, resistance to radiation is a possible cause of recurrence or treatment failure. Recently, DNA damage checkpoint signaling pathway activation after irradiation has received increasing attention. The association between the expression levels and survival outcome was evaluated to find possible therapeutic targets in brain metastasis. Radiosensitivity of human non-small cell lung cancer cell lines was determined by checking their viability after treatment with varying doses of ionizing radiation (IR). The expression of DNA checkpoint proteins was analyzed by Western blots and immunohistochemistry. On the basis of the clinical data for the patients, the association between the expression of the components and patients' survival was investigated. The expression levels of TopBP1 and phosphorylated Chk1 (P-Chk1) protein were higher in radioresistant lung cancer cell lines compared to radiosensitive cell lines. We previously assessed radiation survival of lung cancer cell lines after treating them with Chk1 inhibitor, AZD7762. AZD7762 significantly sensitized both radioresistant and radiosensitive cells to IR. We also observed a strong inverse relationship between progression-free survival (PFS) and expression level of P-Chk1 and TopBP1. This study, which is the first clinical report that connects DNA damage checkpoints and prognosis of brain metastasis, supports these two proteins to be promising targets for overcoming the radioresistance in brain metastasis.
authors.affiliation: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Ho Jun
authors.initials: HJ
authors.lastname: Seol
authors.forename: Hae Yong
authors.initials: HY
authors.lastname: Yoo
authors.forename: Juyoun
authors.initials: J
authors.lastname: Jin
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
authors.forename: Hyeong-Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Yoon
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Choi
authors.forename: Yonghyun
authors.initials: Y
authors.lastname: Kim
authors.forename: Hong Ryull
authors.initials: HR
authors.lastname: Pyo
authors.forename: Do-Hoon
authors.initials: DH
authors.lastname: Lim
authors.forename: Wook
authors.initials: W
authors.lastname: Kim
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Um
authors.forename: Jong Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Jung-Ii
authors.initials: JI
authors.lastname: Lee
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D064007:Ataxia Telangiectasia Mutated Proteins; D001932:Brain Neoplasms / Q000378:metabolism* / Q000532:radiotherapy / Q000556:secondary*; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor / Q000378:metabolism / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D002648:Child; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D017567:Karnofsky Performance Status; D008175:Lung Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011836:Radiation Tolerance; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C113575:Rad17 protein, human; C110513:TOPBP1 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases