端粒酶逆转录酶诱导了质和核酸生物合成在质母细胞瘤中的可针对性改变
bioRxiv : the preprint server for biology
|November 28, 2023
概括
端粒酶逆转录酶 (TERT) 通过通过GCLC升调谷氨 (GSH) 合成来驱动质母细胞瘤的生长. 结合GCLC和像DON这样的谷氨胺代谢抑制剂,可以协同杀死GBM细胞,并在体内缩小瘤.
科学领域:
- 在瘤学瘤学.
- 生物化学 生物化学
- 代谢途径 代谢途径
背景情况:
- 端粒酶逆转录酶 (TERT) 对质母细胞瘤 (GBM) 扩散至关重要.
- 在GBM中,TERT会影响谷氨 (GSH) 的代谢.
- 了解TERT诱导的代谢脆弱性可以揭示新的GBM疗法.
研究的目的:
- 阐明TERT调节GBM中的GSH合成的机制.
- 确定和评估针对GBM中TERT驱动的代谢依赖性的治疗策略.
主要方法:
- 使用siRNA和药理抑制剂 (布氨酸硫胺 - BSO) 抑制谷氨酸-氨酸酶 (GCLC).
- 使用[U-13C]-氨酸的稳定同位素追踪来追踪代谢流量.
- 研究了使用6-diazo-5-oxy-L-norleucine (DON) 和BSO的GCLC,谷氨酸酶 (GLS) 和CAD联合抑制的影响.
- 在实验室和体内使用GBM异种移植模型与JHU-083 (DON前药物) 和BSO评估治疗疗效.
主要成果:
- TERT通过FOXO1上调GCLC表达,从而增强新的GSH合成.
- 抑制GCLC可降低GSH合成和克隆原性,但不会诱导细胞死亡.
- 抑制GCLC激活MYC,导致GLS和CAD的补偿上调.
- 联合抑制GCLC和GLS/CAD (使用BSO和DON) 协同减少GSH和pyrimidine合成,导致GBM细胞死亡.
- 在体内用BSO和JHU-083治疗抑制了瘤代谢,并诱导了GBM异种移植的收缩.
结论:
- TERT表达驱动GBM中的代谢变化,特别是GSH和pyrimidine生物合成.
- 对GCLC和谷氨酸代谢的联合向是GBM治疗的一种合成致命方法.
- 在体内研究证实了抑制GBM这些代谢脆弱性的治疗潜力.
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