| Item type |
文献 / Documents(1) |
| 公開日 |
2021-12-22 |
| アクセス権 |
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アクセス権 |
open access |
| 資源タイプ |
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資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
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資源タイプ |
journal article |
| 出版社版DOI |
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関連識別子 |
https://doi.org/10.3324/haematol.2019.234476 |
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関連名称 |
10.3324/haematol.2019.234476 |
| 出版タイプ |
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出版タイプ |
VoR |
|
出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| タイトル |
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|
タイトル |
TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma |
| タイトル別表記 |
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その他のタイトル |
TAK1 inhibition in myeloma |
| 著者 |
寺町, 順平
天眞, 寛文
日浅, 雅博
オダ, アスカ
Bat-Erdene, Ariunzaya
原田, 武志
中村, 信元
Ashtar, Mohannad
清水, 宗
イワサ, マサミ
曽我部, 公子
大浦, 雅博
藤井, 志朗
賀川, 久美子
三木, 浩和
遠藤, 逸朗
羽地, 達次
松本, 俊夫
安倍, 正博
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| 抄録 |
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内容記述 |
Along with the tumor progression, the bone marrow microenvironment is skewed in multiple myeloma (MM), which underlies the unique pathophysiology of MM and confers aggressiveness and drug resistance in MM cells. TGF-β-activated kinase-1 (TAK1) mediates a wide range of intracellular signaling pathways. We demonstrate here that TAK1 is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition suppresses the activation of NF-κB, p38MAPK, ERK and STAT3 in order to decrease the expression of critical mediators for MM growth and survival, including PIM2, MYC, Mcl-1, IRF4, and Sp1, along with a substantial reduction in the angiogenic factor VEGF in MM cells. Intriguingly, TAK1 phosphorylation was also induced along with upregulation of vascular cell adhesion molecule-1 (VCAM-1) in bone marrow stromal cells (BMSC) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-Β ligand (RANKL) expression by BMSC. TAK1 inhibition effectively impaired MM cell adhesion to BMSC to disrupt the support of MM cell growth and survival by BMSC. Furthermore, TAK1 inhibition suppressed osteoclastogenesis enhanced by RANKL in cocultures of bone marrow cells with MM cells, and restored osteoblastic differentiation suppressed by MM cells or inhibitory factors for osteoblastogenesis overproduced in MM. Finally, treatment with the TAK1 inhibitor LLZ1640-2 markedly suppressed MM tumor growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a promising therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM. |
| 書誌情報 |
en : Haematologica
巻 106,
号 5,
p. 1401-1413,
発行日 2020-04-09
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| 収録物ID |
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収録物識別子タイプ |
ISSN |
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収録物識別子 |
03906078 |
| 収録物ID |
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収録物識別子タイプ |
ISSN |
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収録物識別子 |
15928721 |
| 収録物ID |
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収録物識別子タイプ |
NCID |
|
収録物識別子 |
AA00660912 |
| 出版者 |
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出版者 |
Ferrata Storti Foundation |
| 権利情報 |
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権利情報 |
All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher. |
| EID |
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|
識別子 |
377110 |
| 言語 |
|
|
言語 |
eng |
haematol_106_5_1401.pdf (2.09 MB)
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