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EGLNの活性化に関連した,2-ヒドロキシグルタラートの (R) -エナントイオマーによる変換

Peppi Koivunen¹, Sungwoo Lee, Christopher G Duncan

¹Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.

|February 21, 2012

まとめ

イソチラート脱水素酵素 (IDH) の変異により, (R) - 2 - ヒドロキシグルタレートが生成され,EGLN酵素を阻害し,低酸素誘導因子 (HIF) レベルを低下させることで細胞増殖を促進します. これは,EGLN阻害が潜在的ながん治療法であることを示唆しています.

科学分野:

バイオケミストリーバイオケミストリー
癌生物学癌生物学について
メタボリック・レギュレーション

背景:

サクシネート脱水素酵素 (SDH),フーマレート水素酵素 (FH),イソシテート脱水素酵素 (IDH) の変異は,がん発症と関連しています.
SDHとFHの変異は,代謝物質の蓄積につながり,低酸素誘導因子 (HIF) 調節に関与する酵素を抑制します.
脳腫瘍や白血病におけるIDH変異は, (R) - 2 - ヒドロキシグルタレート ((R) - 2HG) の生成につながります.

研究の目的:

癌の病原性における,変異したIDH酵素によって生成される代謝物である (R) - 2HGの役割を調査する.
(R) - 2HGが腫瘍成長に関連する細胞過程に影響を与えるメカニズムを解明する.
IDH変異がんにおける代謝変化を標的とした潜在的な治療戦略を探求する.

主な方法:

EGLNプロリルヒドロキシラーゼの活性に対する代謝産物の影響の分析.
(R) -2HG.への反応として,低酸素誘導因子 (HIF) レベルの評価.
(R) - 2HG.の存在下におけるアストロサイト増殖とアンカージング独立成長の評価.

主要な成果:

(R) - 2HGは EGLN 活動を刺激することが判明したが, (S) - 2HGはそうではない.
(R) - 2HGによるEGLNの刺激により,HIFのレベルが低下しました.
低濃度のHIFは,ヒトのアストロサイトの増殖と軟アガー増殖を助長した.

結論:

この研究では, (R) - 2HGがIDH変異がんの変容を促進するエナティオマー特異的なメカニズムを特定しました.
IDH変異性腫瘍における (R) - 2HGの蓄積は,HIFレベルを変化させることで病原化に寄与する.
EGLN酵素の阻害は,IDH変異性がんの潜在的な治療方法を示しています.

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