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Updated: Jan 30, 2026

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尼古丁胺胺N-甲基转移酶 (NNMT) 在依赖YAP的干状/半机性前列腺癌中维持对NAMPT抑制的先天敏感性
Ágata Sofia Assunção Carreira1, Marianna Ciuffreda2, Nathakan Thongon1
1University of Trento, CIBIO - Laboratory of Genomic Screening, Trento, Italy.
International journal of biological sciences
|January 29, 2026
概括
我们确定了YAP/尼古丁胺N-甲基转移酶 (NNMT) 轴作为前列腺癌中FK866等NAMPT抑制剂的先天耐药性的关键调节器. 在耐药癌症中,NNMT作为预测对NAD+疗法的反应的生物标志物.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 代谢途径 代谢途径
背景情况:
- 尼古丁胺酸基转移酶 (NAMPT) 抑制剂是有前途的癌症治疗药物,但耐药性限制了它们的使用.
- 对于NAMPT抑制剂的先天性耐药性机制尚不清楚,特别是在晚期前列腺癌亚型中.
- 类似干细胞的抵抗割的前列腺癌 (CRPC-SCL) 呈现出独特的信号依赖性和间酶体特征.
研究的目的:
- 研究前列腺癌中对NAMPT抑制剂的先天性耐药性的机制.
- 为了确定预测对NAMPT向疗法的反应的生物标志物.
- 探索干状,耐治疗的前列腺癌的治疗策略.
主要方法:
- 在前列腺癌细胞系 (PC3,DVL3) 中利用遗传和药理学模型.
- 使用基因沉默 (YAP,NNMT) 和FK866治疗.
- 进行了代谢分析,并分析了临床CRPC-SCL数据集.
- 在小鼠模型中评估 *in vivo* 瘤侵略性.
主要成果:
- 鉴定出YAP/尼古丁胺N-甲基转移酶 (NNMT) 轴是先天FK866敏感性的关键调节者.
- 沉默YAP或NNMT受FK866诱导的亡,ER压力和NAD (H) 枯竭所保护的细胞.
- 表明NNMT活性会耗尽尼古丁胺,使细胞对FK866.6敏感.
- 在临床CRPC-SCL数据中,NNMT上调与介质细胞和耐治疗表型相关.
- 过度表达NNMT的介质前列腺癌细胞对FK866.6的敏感性增加.
结论:
- YAP/NNMT轴决定了前列腺癌中对NAMPT抑制的先天敏感性.
- NNMT 作为 NAD+ 向疗法的预测生物标志物.
- 针对YAP/NNMT/NAMPT轴提供了一种潜在的策略,用于治疗侵袭性,耐治疗性前列腺癌.
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