The survival and proliferation of osteosarcoma cells are dependent on the mitochondrial BIG3-PHB2 complex formation

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Bibliographic Information

Title
The survival and proliferation of osteosarcoma cells are dependent on the mitochondrial BIG3-PHB2 complex formation
Other Title
  • 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
Toki, Shun-ichi
Alias Name
  • 土岐, 俊一
  • トキ, シュンイチ
Author
Yoshimaru, Tetsuro
Alias Name
  • 吉丸, 哲郎
  • ヨシマル, テツロウ
Author
Matsushita, Yousuke
Alias Name
  • 松下, 洋輔
  • マツシタ, ヨウスケ
Author
Aihara, Hitoshi
Alias Name
  • アイハラ, ヒトシ
  • アイハラ, ヒトシ
Author
Ono, Masaya
Alias Name
  • オノ, マサヤ
  • オノ, マサヤ
Author
Tsuneyama, Koichi
Alias Name
  • 常山, 幸一
  • ツネヤマ, コウイチ
Author
Sairyo, Koichi
Alias Name
  • 西良, 浩一
  • サイリョウ, コウイチ
Author
Katagiri, Toyomasa
Alias Name
  • 片桐, 豊雅
  • カタギリ, トヨマサ
University
徳島大学
Types of degree
博士（医学）
Grant ID
甲医第1513号
Degree year
2021-11-25

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.

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