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.

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.;博士(医学)・乙第1345号・平成26年12月3日;© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.;開始ページ : 838;終了ページ : 843;PubMed番号 : http://www.ncbi.nlm.nih.gov/pubmed/24804869

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書名 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.
著作者等 International Gynecological Cancer Society
Kanayama Seiji
Kobayashi Hiroshi
Konishi Noboru
Naruse Katsuhiko
Shimada Keiji
Sudo Tamotsu
Tsuji Yoriko
Uekuri Chiharu
Yamada Yoshihiko
Shigetomi Hiroshi
書名別名 卵巣明細胞腺癌における転写因子HNF-1βはDNA損傷チェックポイント機構の一つであるCHK1タンパクを制御し、抗癌剤耐性を獲得する
出版元 Lippincott Williams & Wilkins
刊行年月 1991-
ページ数 v
ISSN 1048891X
NCID AA10778114
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言語 英語
出版国 アメリカ合衆国
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