パラクリンP2X4刺激によってmTOR依存症を引き起こす大腸腫瘍細胞死
Mark Schmitt1,2,3, Fatih Ceteci1,2, Jalaj Gupta1,2,4
1Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt am Main, Germany.
Nature
|November 17, 2022
まとめ
死亡する癌細胞は,ATPの放出とP2X4受容体の活性化によって,隣接する腫瘍細胞の生存経路を誘発する. これはmTOR阻害剤に対する脆弱性を生み出し,固体腫瘍に対する新しい組み合わせ療法戦略を提供している.
科学分野:
- 腫瘍学
- 細胞生物学
- 分子医学
背景:
- 固体腫瘍は 細胞死と増殖のバランスを通して 成長を維持します
- 死亡する癌細胞は 腫瘍の微小環境で 腫瘍原性修復プログラムを活性化します
- 癌細胞の死亡が隣接する腫瘍細胞と治療への耐性への直接的な影響は不明である.
研究 の 目的:
- 化学療法による癌細胞死が 隣接する腫瘍上皮質に及ぼす直接的な影響を調査する.
- 死亡する細胞が治療に抵抗するメカニズムを解明する.
- 組み合わせ治療の潜在的標的を特定する.
主な方法:
- 患者に由来する結腸直腸腫瘍器官を使用した.
- ATP放出,P2X4受容体活性化,mTORシグナル伝達経路を調査した.
- 反応性酸素種 (ROS) とDNA損傷の役割を評価した.
- 化学療法,P2X4阻害,mTOR阻害を含む評価された組み合わせ療法.
主要な成果:
- 化学療法による細胞死はATPを放出し,P2X4受容体と隣接するがん細胞のmTOR依存生存プログラムを活性化します.
- これによって
- mTOR 依存症
- ROSの生成とDNAの損傷による
- P2X4またはmTORを阻害すると,化学療法と相乗効果があり,重要な細胞死と腫瘍の収縮を引き起こします.
- ROSのスキャニングは,mTORのアクティベーションへの依存を防ぐ.
結論:
- 死亡する癌細胞は 生き残った腫瘍細胞の 抗アポプトシス経路に依存します
- 化学療法と併用してP2X4受容体またはmTOR経路を標的とすることは,有望な組み合わせ療法戦略です.
- このアプローチは,P2X4を発現する上皮腫瘍に特に有効です.
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