向UGCG通过RAB32-介导的内质网膜-线粒体通信使AML细胞对venetoclax敏感
Xiaofan Sun1, Yue Li2, Danqi Pan2
1The First Affiliated Hospital of Jinan University, Guangzhou, China; Department of Hematology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Cell reports
|February 24, 2026
概括
使用 eliglustat 抑制尿素二酸盐 (UDP) - 葡萄糖胺葡萄糖转移酶 (UGCG) 通过诱导胺积累和 ER-线粒体介导的亡,提高了 venetoclax 在急性髓性白血病 (AML) 的疗效.
科学领域:
- 生物化学 生物化学
- 在瘤学瘤学.
- 细胞生物学 细胞生物学
背景情况:
- 尿素二酸盐 (UDP) - 葡萄糖胺糖基转移酶 (UGCG) 糖基化胺,减少其在癌症中的亲亡作用.
- 抑制UGCG使固体瘤对化疗敏感,但其在急性髓性白血病 (AML) 与venetoclax结合中的作用尚不清楚.
研究的目的:
- 研究向UGCG与venetoclax结合治疗AML的疗效.
- 阐明这种组合疗法的潜在分子机制.
主要方法:
- 用 eliglustat.进行UGCG的遗传抑制和药理抑制.
- 在体外和体内评估AML细胞生长,细胞亡和活力.
- 对陶胺水平,内质网膜 (ER) 压力标志物 (GRP78,PERK,CHOP),RAB32,线粒体裂变 (DRP1) 和ER-线粒体通信的分析.
主要成果:
- 单独或与egillustat一起抑制UGCG,抑制AML细胞生长并促进细胞亡.
- 结合伊利格卢斯塔特和维尼托克拉克斯,在原细胞和异种移植模型中显著增加了亡,降低了活力,并抑制了AML.
- 从机制上讲,该组合诱导了胺积累,激活了ER应激通路,并通过RAB32和DRP1.1促进了线粒体裂变.
结论:
- 向UGCG与venetoclax结合,为AML提供了一个有希望的治疗策略.
- 胺积累和随后的ER-线粒体介导的亡是这种组合方法的关键机制.
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