FH变体致病性促进素救援途径依赖性 癌中的癌
Blake R Wilde1,2, Nishma Chakraborty1, Nedas Matulionis1
1Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California.
Cancer discovery
|May 31, 2023
概括
酸盐酸酶 (FH) 基因变异对癌症风险进行了测试. 失去了FH功能导致烟酸的积累,使得癌细胞依赖精氨酸救援途径的生长,提供了一个新的治疗点.
科学领域:
- 生物化学 生物化学
- 在瘤学瘤学.
- 遗传学 遗传学 是一个
背景情况:
- 烟酸酸酶 (FH) 功能的丧失导致烟酸的积累,推动细胞转化.
- 胚性FH变化会导致遗传性乳腺瘤和细胞癌 (HLRCC),使患者易患癌.
- 需要根据与癌症相关的风险对FH变体进行分类.
研究的目的:
- 为了功能性地表征患者相关的不确定意义的FH变体.
- 为了确定FH缺乏癌症中的代谢脆弱性.
- 探索HLRCC的治疗策略.
主要方法:
- 74个FH变种的量化催化效率.
- 生成的HLRCC细胞系表达不同活动的FH变体.
- 与代谢特征和瘤生长相关的烟酸水平 in vivo.
主要成果:
- 超过一半的经过测试的FH变异在酶上是不活跃的,这表明了病原性.
- 酸盐的积累阻断了新的 purin 生物合成,从而使人依赖于 purin 救援.
- 抑制 purin 挽救通路可以减少 HLRCC 瘤生长.
结论:
- 这项研究提供了与HLRCC.相关的FH变异的致病性证据.
- 缺乏FH的癌症在纯素救援途径中表现出脆弱性.
- 向精氨酸救援通路,如6 - 默卡普图,为缺乏FH的癌症提供了一个可翻译的治疗策略.
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