DHODH介导的铁死防御是癌症的可针对性弱点
Chao Mao1, Xiaoguang Liu1, Yilei Zhang1
1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nature
|May 13, 2021
概括
甲基酸脱酶 (DHODH) 作为线粒体防御对铁亡,细胞死亡途径对瘤抑制至关重要. 针对DHODH提供了一种新的癌症治疗策略.
科学领域:
- 细胞死亡机制
- 癌症生物学
- 生物化学
背景情况:
- 铁亡是一种由脂质过氧化驱动的受调细胞死亡形式,作为瘤抑制机制.
- 谷氨过氧化酶4 (GPX4) 和铁死抑制蛋白1 (FSP1) 是防御铁死的关键系统.
- GPX4 抑制剂消耗N- 碳酸- L- 酸盐,影响皮里米丁生物合成和影响铁死.
研究的目的:
- 研究二甲酸脱酶 (DHODH) 在铁死调节中的作用.
- 探索DHODH与GPX4的相互作用及其对癌细胞铁的影响.
- 评估DHODH抑制剂作为潜在的癌症治疗策略.
主要方法:
- 在癌细胞模型中使用GPX4抑制剂和DHODH调节剂 (二酸盐,酸盐,布雷奎纳).
- 评估了铁灭诱导,脂质过氧化和胺生物合成中间体.
- 研究了DHODH在线粒体内的局部和功能.
主要成果:
- 在GPX4低的癌细胞中,DHODH无活化会诱导铁,而在GPX4高的癌细胞中,它会与诱导剂产生协同作用.
- DHODH独立于细胞质GPX4和FSP1,抑制线粒体内膜中的铁.
- DHODH可将乌比奎降解为乌比奎,一种捕捉激素的抗氧化剂,从而防止铁.
- DHODH 抑制剂布雷奎纳通过铁死选择性地抑制了低GPX4的瘤生长.
- 联合布雷奎纳和硫素协同诱导铁和抑制高GPX4的瘤生长.
结论:
- 在线粒体中发现DHODH介导的铁死防御机制.
- DHODH与线粒体GPX4并行作用,以防止铁.
- 针对DHODH是一种有前途的癌症治疗策略,特别是在组合疗法中.
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