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

• Material Type: 博士論文
• Title: TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects
• 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
• No. or year of volume/issue: 1 24
• Volume: 1
• Issue: 24
• Pages: 2124-2137
• ISSN (Periodical Title): ISSN : 2473-9529; ISSN : 2473-9537
• Degree grantor/type: 徳島大学
• Date Granted: 2018-03-23
• Dissertation Number: 甲第3175号
• Degree Type: 博士（歯学）
• 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.
• Format (IMT): application/pdf
• Access Restrictions: インターネット公開
• Related Material (DOI): 10.1182/bloodadvances.2017008813
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 徳島大学 : 徳島大学機関リポジトリ

Table of Contents

https://repo.lib.tokushima-u.ac.jp/files/public/11/111724/20180606145022460473/k3175_abstract.pdf fulltext

https://repo.lib.tokushima-u.ac.jp/files/public/11/111724/20180606145023218006/k3175_review.pdf fulltext

https://repo.lib.tokushima-u.ac.jp/files/public/11/111724/20180606145023683333/k3175_fulltext.pdf fulltext