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

• 資料種別: 博士論文
• ISSN: 2473-9529
• タイトル: TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects
• 巻次・部編番号: 1 24
• 著者・編者: 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
• 著者標目: 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
• 出版事項: The American Society of Hematology
• 出版年月日等: 2017-10-26
• 出版年（W3CDTF）: 2017-10-26
• 並列タイトル等: 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
• タイトル（掲載誌）: Blood Advances
• 授与機関名: 徳島大学
• 授与年月日: 2018-03-23
• 授与年月日（W3CDTF）: 2018-03-23
• 報告番号: 甲第3175号
• 学位: 博士（歯学）
• 博論授与番号: 甲第3175号
• 本文の言語コード: eng
• 件名標目: Immunology; Multiple myeloma; Osteoclastgenesis; TRAIL; TAK1
• 対象利用者: 一般
• 一般注記: 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
• 国立国会図書館永続的識別子: info:ndljp/pid/11116604; https://dl.ndl.go.jp/pid/11116604
• コレクション（共通）: 障害者向け資料
• コレクション（障害者向け資料：レベル1）: テキストデータ
• コレクション（個別）: 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
• 収集根拠: 博士論文（自動収集）
• 受理日（W3CDTF）: 2018-07-03T21:49:10+09:00
• 記録形式（IMT）: application/pdf
• オンライン閲覧公開範囲: 国立国会図書館内限定公開
• デジタル化資料送信: 図書館・個人送信対象外
• 遠隔複写可否（NDL）: 可
• 掲載誌（URI）: https://repo.lib.tokushima-u.ac.jp/111724
• 連携機関・データベース: 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