在MTAP/CDKN2A被删除的癌症中,甲素代谢失调导致对PRMT5的依赖
Konstantinos J Mavrakis1, E Robert McDonald1, Michael R Schlabach1
1Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
概括
没有MTAP的癌症会积累MTA,从而抑制PRMT5. 这造成了对PRMT5抑制的脆弱性,表明PRMT5抑制剂是这些瘤的潜在治疗方法.
科学领域:
- 癌症学
- 生物化学
- 癌症遗传学
背景情况:
- 5甲基氨酸酸酶 (MTAP) 在氨酸救援途径中至关重要.
- 由于接近CDKN2A瘤抑制基因,MTAP基因缺失在人类癌症中很常见.
研究的目的:
- 研究MTAP删除在癌症中的功能后果.
- 确定针对MTAP缺乏的癌症的治疗策略.
主要方法:
- 在390个癌细胞系模型中进行大规模的短发针RNA (shRNA) 查.
- 在MTAP被删除的细胞中分析代谢物积累 (甲基氨酸 - MTA).
- 评估PRMT5甲基转移酶活性和细胞活力.
主要成果:
- 在PRMT5耗尽后,MTAP缺乏的癌细胞的活力受损.
- 在MTAP被删除的细胞中积累的MTA抑制了PRMT5甲基转移酶的活性.
- 删除MTAP使细胞对PRMT5抑制敏感;重新引入MTAP可以挽救这种依赖.
结论:
- 在被删除MTAP的癌症中,MTA积累导致PRMT5的低形态,从而对PRMT5抑制产生敏感性.
- 对于MTAP/CDKN2A被删除的瘤来说,PRMT5抑制剂是一个有希望的治疗途径.
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