ID | 116529 |
Title Alternative | TAK1 inhibition in myeloma
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Author |
Teramachi, Jumpei
Tokushima University
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Hiasa, Masahiro
Tokushima University
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Oda, Asuka
Tokushima University
Bat-Erdene, Ariunzaya
Tokushima University|Mongolian National University of Medical Sciences
Nakamura, Shingen
Tokushima University
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Ashtar, Mohannad
Tokushima University
Iwasa, Masami
Tokushima University
Fujii, Shiro
Tokushima University
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Miki, Hirokazu
Tokushima University
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Endo, Itsuro
Tokushima University
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Haneji, Tatsuji
Tokushima University
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Matsumoto, Toshio
Tokushima University
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Abe, Masahiro
Tokushima University
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Content Type |
Journal Article
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Description | 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.
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Journal Title |
Haematologica
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ISSN | 03906078
15928721
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NCID | AA00660912
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Publisher | Ferrata Storti Foundation
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Volume | 106
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Issue | 5
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Start Page | 1401
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End Page | 1413
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Published Date | 2020-04-09
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Rights | 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.
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EDB ID | |
DOI (Published Version) | |
URL ( Publisher's Version ) | |
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language |
eng
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TextVersion |
Publisher
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departments |
Oral Sciences
University Hospital
Medical Sciences
Institute of Advanced Medical Sciences
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