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与EGLN激活相关的2-基氨酸的 (R) - 异构体转化

Peppi Koivunen¹, Sungwoo Lee, Christopher G Duncan

¹Biocenter Oulu, Department of Medical Biochemistry and Molecular Biology, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.

|February 21, 2012

概括

异酸脱酶 (IDH) 中的突变产生 (R) -2-基酸盐,通过抑制EGLN酶和降低缺氧诱导因子 (HIF) 水平,增强细胞增殖. 这表明EGLN抑制是潜在的癌症治疗方法.

科学领域:

生物化学生物化学
癌症生物学癌症生物学
代谢调节代谢调节代谢调节

背景情况:

糖酸脱酶 (SDH),烟酸酶 (FH) 和异酸脱酶 (IDH) 的突变与癌症的发展有关.
SDH和FH突变导致代谢物积累,抑制参与低氧诱导因子 (HIF) 调节的酶.
在脑瘤和白血病中发生的IDH突变导致 (R) - 2 - 基酸盐 (R) - 2HG) 的产生.

研究的目的:

研究由突变的IDH酶产生的代谢物 (R) - 2HG在癌症发病过程中的作用.
阐明 (R) - 2HG影响与瘤生长相关的细胞过程的机制.
探索潜在的治疗策略,针对IDH突变癌症中的代谢变化.

主要方法:

对EGLN prolyl氧酶活性对代谢物效应的分析.
评估低氧诱导因子 (HIF) 水平,以应对 (R) - 2HG.
在存在 (R) - 2HG.时评估星球细胞的增殖和独立于定位的生长.

主要成果:

发现 (R) - 2HG,但不是 (S) - 2HG,可以刺激EGLN活动.
通过 (R) - 2HG刺激EGLN导致HIF水平降低.
降低HIF水平增强了人类天体细胞的增殖和软生长.

结论:

这项研究确定了一种对表原体特异的机制,其中 (R) - 2HG促进了IDH突变癌症的转化.
在IDH突变瘤中 (R) - 2HG的积累通过改变HIF水平,有助于致病.
抑制EGLN酶为IDH突变癌症提供了潜在的治疗途径.

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