Nrf2の活性化は,Bach1の分解を阻害することによって,肺がんの転移を促進する

Luca Lignitto¹, Sarah E LeBoeuf², Harrison Homer¹

¹Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New York University School of Medicine, New York, NY 10016, USA.

Cell

|July 2, 2019

まとめ

肺がんにおけるNrf2の蓄積は,ヘムを誘導することによって,転移前因子Bach1を安定させる. ヘム生成を阻害することで,Bach1の安定化と肺がんの転移を阻害し,新たな治療戦略を示唆している.

科学分野:

腫瘍学
分子生物学
生物化学

背景:

ヒトの肺がんの約30%には,Keap1またはNfe2l2の変異があり,Nuclear factor erythroid 2-関連因子2 (Nrf2) の安定化につながる.
Nrf2は酸化性ホメオスタシスを制御する上で重要な役割を果たしますが,癌の進行におけるその役割は複雑です.
バッハマン (Bach1) は,腫瘍転移を促進する転写因子である.

研究の目的:

肺がんの転移における Nrf2 蓄積の役割を調査する.
Nrf2がBach1の安定性を影響するメカニズムを解明する.
肺がんにおけるNrf2-Bach1軸の治療の可能性を調査する.

主な方法:

Keap1またはNfe2l2変異を有する肺がんのマウスモデルを使用した.
ヘム,Bach1,F- ボックスタンパク質22 (Fbxo22) とヘム酸素酶1 (Ho1) の相互作用を研究した.
人間の転移性肺がん組織と患者の生存データを分析した.

主要な成果:

ヘムはFbxo22媒介によるBach1分解を促進する.
肺がんにおけるNrf2の蓄積は,ヘムを分解するHo1を誘導することによってBach1を安定させる.
Keap1またはFbxo22の喪失と薬学的Ho1阻害は,マウスモデルにおける肺がん転移に影響を与えました.
高濃度のHo1とBach1は,ヒト肺がん患者の生存率と転移の低下と相関しています.

結論:

肺がんにおけるNrf2の活性化は,Ho1経路を通じてBach1を安定させ,それによってヘムおよびFbxo22媒介による分解を抑制することによって転移を促進します.
Ho1の阻害剤は肺がんの転移を防ぐために有望な治療戦略です.

キーワード:

バッハ CRL複合体 Fボックスタンパク質 Fbxo22 についてヘーム Ho1 阻害剤キープ1 Nrf2 についてクリン-RINGユビキチンリガゼ肺がん転移するユビキチン

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