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ID 109988
Title Alternative
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
Author
Bat-Erdene, Ariunzaya Tokushima University
Oda, Asuko Tokushima University
Amachi, Ryota Tokushima University
Iwasa, Masami Tokushima University
Sogabe, Kimiko Tokushima University
Keywords
multiple myeloma
panobinostat
proteasome inhibitors
caspase-8
Sp1
Content Type
Thesis or Dissertation
Description
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.
Journal Title
Oncotarget
ISSN
19492553
Publisher
Impact Journals
Volume
7
Issue
48
Start Page
79064
End Page
79075
Published Date
2016-10-12
Remark
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。
Rights
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
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3002号
Diploma Number
甲医第1307号
Granted Date
2016-11-24
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
University Hospital
Medical Sciences
Oral Sciences