title: Inhibition of cell death and induction of G2 arrest accumulation in human ovarian clear cells by HNF-1β transcription factor: chemosensitivity is regulated by checkpoint kinase CHK1.
abstract: OBJECTIVE
  Appropriate cell cycle checkpoints are essential for the maintenance of normal cells and chemosensitivity of cancer cells. Clear cell adenocarcinoma (CCA) of the ovary is highly resistant to chemotherapy. Hepatocyte nuclear factor-1β (HNF-1β) is known to be overexpressed in CCA, but its role and clinical significance is unclear. We investigated the role of HNF-1β in regulation of the cell cycle in CCA.
  
  
  METHODS
  To clarify the effects of HNF-1β on cell cycle checkpoints, we compared the cell cycle distribution and the expression of key proteins involved in CCA cells in which HNF-1β had been stably knocked down and in vector-control cell lines after treatment with bleomycin. HNF-1β (+) cells were arrested in G2 phase because of DNA damage.
  
  
  RESULTS
  HNF-1β (-) cells died because of a checkpoint mechanism. G2 arrest of HNF-1β (+) cells resulted from sustained CHK1 activation, a protein that plays a major role in the checkpoint mechanism. HNF-1β (+) cells were treated with a CHK1 inhibitor after bleomycin treatment. Flow cytometric analysis of the cell cycle demonstrated that DNA damage-induced G2-arrested cells were released from the checkpoint and killed by a CHK1 inhibitor.
  
  
  CONCLUSIONS
  The chemoresistance of CCA may be due to aberrant retention of the G2 checkpoint through overexpression of HNF-1β. This is the first study demonstrating cell cycle regulation and chemosensitization by a CHK1 inhibitor in CCA.
authors.affiliation: *Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara; †Section of Translational Research, Hyogo Cancer Center, Akashi, Hyogo; ‡Department of Pathology, Nara Medical University, Kashihara, Nara; and §Department of Obstetrics and Gynecology, Yao Municipal Hospital, Yao-city, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shigetomi
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Sudo
authors.forename: Keiji
authors.initials: K
authors.lastname: Shimada
authors.forename: Chiharu
authors.initials: C
authors.lastname: Uekuri
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Tsuji
authors.forename: Seiji
authors.initials: S
authors.lastname: Kanayama
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Naruse
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Noboru
authors.initials: N
authors.lastname: Konishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D016195:G2 Phase; D051539:Hepatocyte Nuclear Factor 1-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: C496495:HNF1B protein, human; D034741:RNA, Small Interfering; D051539:Hepatocyte Nuclear Factor 1-beta; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1