TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects 1 24

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TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects 24

Persistent ID (NDL): info:ndljp/pid/11116604

Material type: 博士論文

Author: Tenshin, Hirofumiほか

Publisher: The American Society of Hematology

Publication date: 2017-10-26

Material Format: Digital

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Name of awarding university/degree: 徳島大学,博士（歯学）

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Note (General)：: Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) agonists induce tumor-specific apoptosis indicating that they may be an attractive the...

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Material Type: 博士論文
ISSN: 2473-9529
Title: TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects
Volume: 1 24
Author/Editor: Tenshin, Hirofumi
Teramachi, Jumpei
Oda, Asuka
Amachi, Ryota
Hiasa, Masahiro
Bat-Erdene, Ariunzaya
Watanabe, Keiichiro
Iwasa, Masami
Harada, Takeshi
Fujii, Shiroh
Kagawa, Kumiko
Sogabe, Kimiko
Nakamura, Shingen
Miki, Hirokazu
Kurahashi, Kiyoe
Yoshida, Sumiko
Aihara, Kenichi
Endo, Itsuro
Tanaka, Eiji
Matsumoto, Toshio
Abe, Masahiro
Author Heading: Tenshin, Hirofumi
Teramachi, Jumpei
Oda, Asuka
Amachi, Ryota
Hiasa, Masahiro
Bat-Erdene, Ariunzaya
Watanabe, Keiichiro
Iwasa, Masami
Harada, Takeshi
Fujii, Shiroh
Kagawa, Kumiko
Sogabe, Kimiko
Nakamura, Shingen
Miki, Hirokazu
Kurahashi, Kiyoe
Yoshida, Sumiko
Aihara, Kenichi
Endo, Itsuro
Tanaka, Eiji
Matsumoto, Toshio
Abe, Masahiro
Publication, Distribution, etc.: The American Society of Hematology
Publication Date: 2017-10-26
Publication Date (W3CDTF): 2017-10-26
Alternative Title: TAK1阻害はTRAILの抗骨髄腫作用を増強するともに骨吸収促進活性を抑制活性に変換する
MODULATION OF TRAIL ACTION BY TAK1 INHIBITION
Periodical title: Blood Advances
Degree grantor/type: 徳島大学
Date Granted: 2018-03-23
Date Granted (W3CDTF): 2018-03-23
Dissertation Number: 甲第3175号
Degree Type: 博士（歯学）
Conferring No. (Dissertation): 甲第3175号
Text Language Code: eng
Subject Heading: Immunology
Multiple myeloma
Osteoclastgenesis
TRAIL
TAK1
Target Audience: 一般
Note (General): Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) agonists induce tumor-specific apoptosis indicating that they may be an attractive therapeutic strategy against cancers, including multiple myeloma (MM). Osteoclastogenesis is highly induced in MM, which in turn enhances MM growth, thereby forming a vicious cycle between MM tumor expansion and bone destruction. However, the effects of TRAIL on MM-enhanced osteoclastogenesis remain largely unknown. Here, we show that TRAIL induced apoptosis in MM cells, but not in osteoclasts (OCs), and that it rather facilitated receptor activator of NF-kB ligand–induced osteoclastogenesis along with upregulation of cellular FLICE inhibitory protein (c-FLIP). TRAIL did not induce death-inducing signaling complex formation in OCs, but formed secondary complex (complex II) with the phosphorylation of transforming growth factor b–activated kinase-1 (TAK1), and thus activated NF-kB signaling. c-FLIP knockdown abolished complex II formation, thus permitting TRAIL induction of OC cell death. The TAK1 inhibitor LLZ1640-2 abrogated the TRAIL-induced c-FLIP upregulation and NF-kB activation, and triggered TRAIL-induced caspase-8 activation and cell death in OCs. Interestingly, the TRAIL-induced caspase-8 activation caused enzymatic degradation of the transcription factor Sp1 to noticeably reduce c-FLIP expression, which further sensitized OCs to TRAIL-induced apoptosis. Furthermore, the TAK1 inhibition induced antiosteoclastogenic activity by TRAIL even in cocultures with MM cells while potentiating TRAIL’s anti-MM effects. These results demonstrated that osteoclastic lineage cells use TRAIL for their differentiation and activation through tilting caspase-8–dependent apoptosis toward NF-kB activation, and that TAK1 inhibition subverts TRAIL-mediated NF-kB activation to resume TRAIL-induced apoptosis in OCs while further enhancing MM cell death in combination with TRAIL.
DOI: info:doi/10.1182/bloodadvances.2017008813
https://doi.org/info:doi/10.1182/bloodadvances.2017008813
Persistent ID (NDL): info:ndljp/pid/11116604
https://dl.ndl.go.jp/pid/11116604
Collection: 障害者向け資料
Collection (Materials For Handicapped People:1): テキストデータ
Collection (particular): 国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文
https://dl.ndl.go.jp/collections/A00014
Acquisition Basis: 博士論文（自動収集）
Date Accepted (W3CDTF): 2018-07-03T21:49:10+09:00
Format (IMT): application/pdf
Access Restrictions: 国立国会図書館内限定公開
Service for the Digitized Contents Transmission Service: 図書館・個人送信対象外
Availability of remote photoduplication service: 可
Periodical Title (URI): https://repo.lib.tokushima-u.ac.jp/111724
Data Provider (Database): 国立国会図書館 : 国立国会図書館デジタルコレクション
https://dl.ndl.go.jp