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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
Author
Oda, Asuka Tokushima University
Amachi, Ryota Tokushima University
Bat-Erdene, Ariunzaya Tokushima University
Iwasa, Masami Tokushima University
Sogabe, Kimiko Tokushima University
Keywords
Immunology
Multiple myeloma
Osteoclastgenesis
TRAIL
TAK1
Content Type
Thesis or Dissertation
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.
Journal Title
Blood Advances
ISSN
24739529
24739537
Publisher
The American Society of Hematology
Volume
1
Issue
24
Start Page
2124
End Page
2137
Published Date
2017-10-26
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
TextVersion
ETD
MEXT report number
甲第3175号
Diploma Number
甲口第432号
Granted Date
2018-03-23
Degree Name
Doctor of Dental Science
Grantor
Tokushima University
departments
Oral Sciences
University Hospital
Medical Sciences
Institute of Advanced Medical Sciences