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TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma TAK1 inhibition in myeloma 20515986 寺町, 順平 テラマチ, ジュンペイ Teramachi, Jumpei 寺町 テラマチ Teramachi 順平 ジュンペイ Jumpei 天眞, 寛文 テンシン, ヒロフミ Tenshin, Hirofumi 天眞 テンシン Tenshin 寛文 ヒロフミ Hirofumi 90511337 日浅, 雅博 ヒアサ, マサヒロ Hiasa, Masahiro 日浅 ヒアサ Hiasa 雅博 マサヒロ Masahiro オダ, アスカ オダ, アスカ Oda, Asuka Bat-Erdene, Ariunzaya 原田, 武志 ハラダ, タケシ Harada, Takeshi 原田 ハラダ Harada 武志 タケシ Takeshi 10511321 中村, 信元 ナカムラ, シンゲン Nakamura, Shingen 中村 ナカムラ Nakamura 信元 シンゲン Shingen Ashtar, Mohannad 清水, 宗 シミズ, ソウ Shimizu, So イワサ, マサミ イワサ, マサミ Iwasa, Masami 曽我部, 公子 ソガベ, キミコ Sogabe, Kimiko 曽我部 ソガベ Sogabe 公子 キミコ Kimiko 大浦, 雅博 オオウラ, マサヒロ Oura, Masahiro 大浦 オオウラ Oura 雅博 マサヒロ Masahiro 00618473 藤井, 志朗 フジイ, シロウ Fujii, Shiroh 藤井 フジイ Fujii 志朗 シロウ Shiroh 賀川, 久美子 カガワ, クミコ Kagawa, Kumiko 50511333 三木, 浩和 ミキ, ヒロカズ Miki, Hirokazu 三木 ミキ Miki 浩和 ヒロカズ Hirokazu 10432759 遠藤, 逸朗 エンドウ, イツロウ Endo, Itsuro 遠藤 エンドウ Endo 逸朗 イツロウ Itsuro 50156379 羽地, 達次 ハネジ, タツジ Haneji, Tatsuji 羽地 ハネジ Haneji 達次 タツジ Tatsuji 20157374 松本, 俊夫 マツモト, トシオ Matsumoto, Toshio 松本 マツモト Matsumoto 俊夫 トシオ Toshio 80263812 安倍, 正博 アベ, マサヒロ Abe, Masahiro 安倍 アベ Abe 正博 マサヒロ Masahiro open access 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. 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. Ferrata Storti Foundation 2020-04-09 eng journal article VoR 377110 https://tokushima-u.repo.nii.ac.jp/records/2009431 https://doi.org/10.3324/haematol.2019.234476 10.3324/haematol.2019.234476 03906078 15928721 AA00660912 Haematologica 106 5 1401 1413 https://tokushima-u.repo.nii.ac.jp/record/2009431/files/haematol_106_5_1401.pdf application/pdf 2.09 MB 2021-12-22