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ID 116580
Title Alternative
骨肉腫細胞の生存と増殖はミトコンドリア局在BIG3-PHB2複合体形成に依存する
Author
Aihara, Hitoshi Tokushima University
Ono, Masaya National Cancer Center Research Institute
Keywords
BIG3
mitochondria
osteosarcoma
peptide inhibitor
PHB2
Content Type
Thesis or Dissertation
Description
Previous studies reported the critical role of the brefeldin A–inhibited guanine nucleotide exchange protein 3–prohibitin 2 (BIG3-PHB2) complex in modulating estrogen signaling activation in breast cancer cells, yet its pathophysiological roles in osteosarcoma (OS) cells remain elusive. Here, we report a novel function of BIG3-PHB2 in OS malignancy. BIG3-PHB2 complexes were localized mainly in mitochondria in OS cells, unlike in estrogen-dependent breast cancer cells. Depletion of endogenous BIG3 expression by small interfering RNA (siRNA) treatment led to significant inhibition of OS cell growth. Disruption of BIG3-PHB2 complex formation by treatment with specific peptide inhibitor also resulted in significant dose-dependent suppression of OS cell growth, migration, and invasion resulting from G2/M-phase arrest and in PARP cleavage, ultimately leading to PARP-1/apoptosis-inducing factor (AIF) pathway activation–dependent apoptosis in OS cells. Subsequent proteomic and bioinformatic pathway analyses revealed that disruption of the BIG3-PHB2 complex might lead to downregulation of inner mitochondrial membrane protein complex activity. Our findings indicate that the mitochondrial BIG3-PHB2 complex might regulate PARP-1/AIF pathway-dependent apoptosis during OS cell proliferation and progression and that disruption of this complex may be a promising therapeutic strategy for OS.
Journal Title
Cancer Science
ISSN
13497006
Publisher
Wiley|Japanese Cancer Association
Volume
112
Issue
10
Start Page
4208
End Page
4219
Published Date
2021-08-07
Remark
内容要旨・審査要旨・論文本文の公開
本論文は,著者Shunichi Toki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。
Rights
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License( https://creativecommons.org/licenses/by-nc/4.0/ ), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
EDB ID
DOI (Published Version)
URL ( Publisher's Version )
FullText File
language
eng
TextVersion
ETD
MEXT report number
甲第3561号
Diploma Number
甲医第1513号
Granted Date
2021-11-25
Degree Name
Doctor of Medical Science
Grantor
Tokushima University
departments
Medical Sciences
Institute of Advanced Medical Sciences