NRF2は,臓がんにおけるmRNA翻訳を調節することにより,腫瘍の維持を促進する
Iok In Christine Chio1, Seyed Mehdi Jafarnejad2, Mariano Ponz-Sarvise1
1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA.
Cell
|August 2, 2016
まとめ
核因子エリソイド2関連因子2 (NRF2) は,mRNA翻訳を調節することによって,臓がんの成長を誘導する. AKTとグルタチオンの経路をターゲットにすることで 臓がんの治療に 有望な合成致死戦略が生まれます
科学分野:
- 腫瘍学
- 分子生物学
- 癌 研究
背景:
- 臓がんは致命的な悪性腫瘍であり,有効な治療法は限られている.
- 腫瘍性KrasはNRF2を誘発し,臓および肺がんの発症を促すことが以前示された.
- 既定の臓がん増殖の維持におけるNRF2の役割は調査された.
研究 の 目的:
- 臓がんの増殖におけるNRF2の役割を明らかにする.
- NRF2が癌細胞の成長を制御するメカニズムを特定する.
- NRF2媒介経路を標的とした潜在的な治療戦略を探求する.
主な方法:
- 臓がん細胞増殖に対するNRF2の必要性を調査した.
- オトクリン表皮成長因子受容体 (EGFR) 信号伝達に対するNRF2喪失の影響を分析した.
- キャップ依存およびキャップ独立メカニズムを含むmRNA翻訳の評価された変化
- 臨床前モデルのAKTとグルタチオンの抗酸化経路の組み合わせを評価.
主要な成果:
- NRF2は,臓がん細胞の増殖を維持するために不可欠です.
- NRF2の喪失は自己決定性EGFRの信号伝達を妨害し,mRNAの翻訳を阻害する.
- NRF2の喪失時に特定の変換調節タンパク質が酸化することが判明した.
- AKTとグルタチオンの結合抑制は,ex vivoとin vivoで腫瘍の成長を効果的に抑制しました.
結論:
- NRF2は,mRNAの翻訳を制御することによって,臓がんの増殖を制御する.
- NRF2シグナル伝達の障害はEGFRシグナル伝達とタンパク質翻訳に影響する.
- AKTとグルタチオンの結合標的は 臓がんに対する強力な合成致死戦略です
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