直近一年間の累計
アクセス数 : ?
ダウンロード数 : ?
ID 109988
タイトル別表記
パノビノスタットとプロテアソーム阻害薬は骨髄腫細胞の増殖と生存に必須の転写因子Sp1を相乗的に標的にする
著者
バット エルデネ, アリウンザヤ 徳島大学大学院医科学教育部(医学専攻)
Oda, Asuko Tokushima University
天知, 良太 Tokushima University
Iwasa, Masami Tokushima University
キーワード
multiple myeloma
panobinostat
proteasome inhibitors
caspase-8
Sp1
資料タイプ
学位論文
抄録
Panobinostat, a pan-deacetylase inhibitor, synergistically elicits cytotoxic activity against myeloma (MM) cells in combination with the proteasome inhibitor bortezomib. Because precise mechanisms for panobinostat’s anti-MM action still remain elusive, we aimed to clarify the mechanisms of anti-MM effects of panobinostat and its synergism with proteasome inhibitors. Although the transcription factor Sp1 was overexpressed in MM cells, the Sp1 inhibitor terameprocol induced MM cell death in parallel with reduction of IRF4 and cMyc. Panobinostat induced activation of caspase-8, which was inversely correlated with reduction of Sp1 protein levels in MM cells. The panobinostat-mediated effects were further potentiated to effectively induce MM cell death in combination with bortezomib or carfilzomib even at suboptimal concentrations as a single agent. Addition of the caspase-8 inhibitor z-IETD-FMK abolished the Sp1 reduction not only by panobinostat alone but also by its combination with bortezomib, suggesting caspase-8-mediated Sp1 degradation. The synergistic Sp1 reduction markedly suppressed Sp1-driven prosurvival factors, IRF4 and cMyc. Besides, the combinatory treatment reduced HDAC1, another Sp1 target, in MM cells, which may potentiate HDAC inhibition. Collectively, caspase-8-mediated post-translational Sp1 degradation appears to be among major mechanisms for synergistic anti-MM effects of panobinostat and proteasome inhibitors in combination.
掲載誌名
Oncotarget
ISSN
19492553
出版者
Impact Journals
7
48
開始ページ
79064
終了ページ
79075
発行日
2016-10-12
備考
内容要旨・審査要旨・論文本文の公開:
内容要旨・審査要旨 : LID201701101003.pdf
論文本文 : LID201701101004.pdf
本論文は, 著者Ariunzaya Bat-Erdeneの学位論文として提出され, 学位審査・授与の対象となっている。
権利情報
Copyright: © 2016 Bat-Erdene et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
博士論文全文を含む
文科省報告番号
甲第3002号
学位記番号
甲医第1307号
学位授与年月日
2016-11-24
学位名
博士(医学)
学位授与機関
徳島大学
部局
病院
医学系
歯学系