ID | 111724 |
Title Alternative | 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
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Author |
Teramachi, Jumpei
Tokushima University
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Oda, Asuka
Tokushima University
Amachi, Ryota
Tokushima University
Hiasa, Masahiro
Tokushima University
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Bat-Erdene, Ariunzaya
Tokushima University
Watanabe, Keiichiro
Tokushima University
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Iwasa, Masami
Tokushima University
Fujii, Shiroh
Tokushima University
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Nakamura, Shingen
Tokushima University
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Miki, Hirokazu
Tokushima University
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Yoshida, Sumiko
Tokushima University
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Aihara, Kenichi
Tokushima University
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Endo, Itsuro
Tokushima University
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Tanaka, Eiji
Tokushima University
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Matsumoto, Toshio
Tokushima University
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Abe, Masahiro
Tokushima University
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Keywords | Immunology
Multiple myeloma
Osteoclastgenesis
TRAIL
TAK1
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Content Type |
Thesis or Dissertation
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Description | 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.
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Journal Title |
Blood Advances
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ISSN | 24739529
24739537
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Publisher | The American Society of Hematology
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Volume | 1
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Issue | 24
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Start Page | 2124
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End Page | 2137
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Published Date | 2017-10-26
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Remark | 内容要旨・審査要旨・論文本文の公開
本論文は, 著者Hirofumi Tenshinの学位論文として提出され, 学位審査・授与の対象となっている。 |
EDB ID | |
DOI (Published Version) | |
URL ( Publisher's Version ) | |
FullText File | |
language |
eng
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TextVersion |
ETD
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MEXT report number | 甲第3175号
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Diploma Number | 甲口第432号
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Granted Date | 2018-03-23
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Degree Name |
Doctor of Dental Science
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Grantor |
Tokushima University
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departments |
Oral Sciences
University Hospital
Medical Sciences
Institute of Advanced Medical Sciences
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