Hsp90の高親和性コンフォームは,Hsp90阻害剤に腫瘍選択性を授与する
Adeela Kamal1, Lia Thao, John Sensintaffar
1Conforma Therapeutics Corporation, 9393 Towne Centre Drive, Suite 240, San Diego, California 92121, USA.
Nature
|September 26, 2003
まとめ
癌細胞の熱ショックタンパク質90 (Hsp90) は,正常細胞よりも17-AAG薬に対する100倍以上の親和性を有する. この違いは,腫瘍のHsp90が活性化複合体の中にあり,潜在的ながん治療標的を提供しているためです.
科学分野:
- 分子生物学は分子生物学である.
- 腫瘍学 腫瘍学
- バイオケミストリー バイオケミストリー
背景:
- 熱ショックタンパク質90 (Hsp90) は,腫瘍性シグナル伝達タンパク質の機能に不可欠な分子チャペロンです.
- 17 - アリラミノゲルダナミシン (17-AAG) のようなHsp90阻害剤は,これらのクライアントタンパク質の分解を誘導し,選択的な癌細胞殺戮を示します.
- Hsp90阻害剤のこの腫瘍選択性の分子基礎は,ほとんど不明のままである.
研究 の 目的:
- Hsp90阻害剤の腫瘍選択性の分子基礎を調査する.
- 腫瘍細胞と正常細胞の17-AAGとHsp90の結合親和を比較する.
主な方法:
- 腫瘍および正常な細胞からの17-AAGのHsp90への結合親和性を測定するための生化学的測定法.
- 腫瘍と正常細胞におけるHsp90複合体の形成とATPアゼ活性に関する分析.
- Hsp90チャペロン複合体のインビトロ再構成.
主要な成果:
- 腫瘍細胞から得られたHsp90は,正常細胞から得られたHsp90と比較して,17-AAGに対する結合親和性が100倍高いことを示した.
- 腫瘍のHsp90は,高ATPase活性を持つ活性マルチチャペロン複合体で発見され,正常なHsp90は潜伏状態で,複合体を持たない状態でした.
- Hsp90をチャペロン複合体に再構成すると,in vitroでは17-AAGへの結合親和性が増加し,ATPase活性が強化されます.
結論:
- 腫瘍細胞は,Hsp90複合体を活性化され,高親和性コンフォームで持っており,悪性腫瘍の進行を促進します.
- この活性化されたHsp90複合体は,がん治療の潜在的ユニークな治療目標です.
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