トランスラトーム制御ダイエットの改造とその腫瘍形成への影響

Haojun Yang^1,2, Vincenzo Andrea Zingaro^1,2, James Lincoff^3,4

¹Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, CA, USA.

Nature

|August 14, 2024

まとめ

禁食はAMPK-MNK-eIF4E経路を通じた選択的翻訳制御を誘発し,ケトゲネシスを強化する. この経路は脂肪酸と関連しておりガン治療の標的となる可能性があります

科学分野:

メタボリックシグナル
分子生物学
癌の研究

背景:

禁食は健康に有益ですがタンパク質の変換と代謝プログラムに影響する分子メカニズムは完全に理解されていません
全球的なタンパク質変換は断食中に減少しますが,特に肝細胞では特定の細胞適応が起こります.

研究の目的:

断食がタンパク質の変換を調節し,代謝プログラムを確立する分子機構を明らかにする.
禁食誘発ケトゲネシスと脂質代謝に関わる重要な信号伝達経路を特定する.
これらの経路を標的にすることで治療の可能性を探るためです

主な方法:

禁食中の肝細胞トランスラトームの分析
遺伝子翻訳の制御におけるリン酸化エウカリオット翻訳開始因子4E (P-eIF4E) の役割の調査.
P-eIF4E経路の遺伝的および薬学的阻害を利用する.
脂肪酸がAMP活性化タンパク質キナーゼ (AMPK) とMAPキナーゼ相互作用タンパク質キナーゼ (MNK) のシグナル伝達に及ぼす影響を研究する.
臓腫瘍の成長に対するP-eIF4E抑制の影響をケトジックダイエットモデルで評価する.

主要な成果:

断食は肝細胞内のトランスラトームを選択的に再構成し,全体的なトランスレーションを低下させ,特定のタンパク質を上昇させます.
ユカリオット変換開始因子4E (P-eIF4E) の酸化は,断食によって誘発され,脂質分解とケトゲネシスの遺伝子を制御する.
脂肪酸はAMPK-MNK-eIF4E信号軸を活性化し,脂質代謝を翻訳制御とケトゲネシスと結びつける.
P-eIF4Eの抑制はケトゲネシスを阻害し,ケトゲン的なダイエットでは臓腫瘍の成長を抑制する.

結論:

新しい脂肪酸誘発信号経路 (AMPK-MNK-eIF4E) は,脂質代謝と選択的翻訳制御を結びつけ,ケトゲネシスを誘発する.
この経路はケトン体をエネルギー源として利用する癌の治療対象となる可能性があります
P-eIF4EをeFT508のような阻害剤で標的化することは,特にケトジックダイエットと併用して,がん治療に有望であることが示されています.

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