急性骨髓性白血病中的线粒体将ATP水解以抵抗化疗
James T Hagen1,2, Mclane M Montgomery3,1,2, Raphael T Aruleba3
1Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC.
bioRxiv : the preprint server for biology
|April 25, 2024
概括
急性髓性白血病 (AML) 的癌细胞消耗ATP以维持线粒体功能,与健康细胞不同. 这种独特的生物能量脆弱性可以通过化疗准,以克服治疗耐药性.
科学领域:
- 生物化学 生物化学
- 细胞生物学 细胞生物学
- 在瘤学瘤学.
背景情况:
- 针对氧化酸化 (OxPhos) 的治疗方法由于无法区分健康和癌症线粒体而取得有限的成功.
- 急性髓性白血病 (AML) 细胞在其线粒体内具有独特的生物能量机制.
研究的目的:
- 为了识别和描述AML线粒体中独特的新生物能机制.
- 探索针对这种机制的潜力,以克服AML中的化疗耐药性.
主要方法:
- 在AML细胞和健康对照中研究了线粒体生物能学.
- 使用venetoclax抑制BCL-2,以评估OxPhos流和线粒体膜潜力.
- 研究了矩阵ATP消耗和F1-ATPase抑制剂ATP5IF1在venetoclax耐药性的作用.
- 在AML细胞中进行ATP5IF1的基因淘汰和过度表达研究.
主要成果:
- 发现AML线粒体消耗ATP以维持内膜两极化,与与呼吸与ATP合成结合的健康细胞不同.
- 威尼托克拉克斯治疗消除了OxPhos流量,但在AML细胞中维持了线粒体膜潜力,这取决于矩阵ATP消耗.
- 线粒体ATP消耗在venetoclax-耐火性AML细胞中增加,这是由于呼吸复合体和ATP5IF1.1.的下调.
- ATP5IF1 knockdown诱导了venetoclax耐药性,而其过度表达使AML细胞对venetoclax敏感.
结论:
- 矩阵ATP消耗在AML中代表了癌细胞内在的生物能量脆弱性.
- 这一漏洞在线粒体破坏性化疗的背景下是可操作的,为克服治疗耐药性的潜在策略提供了一个潜在的策略.
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