Cell-permeating α-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells
Cell-permeating α-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells
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DOI：
10.1128/mcb.01927-06
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发表时间：
2007-05-01
影响因子：
5.3
通讯作者：
Gottlieb, Eyal
中科院分区：
文献类型：
--
作者：
MacKenzie, Elaine D.;Selak, Mary A.;Gottlieb, Eyal
琥珀酸脱氢酶(SDH)和富马酸水合酶(FH)是三羧酸(TCA)循环的组成部分，也是肿瘤抑制因子。SDH或FH的缺失会导致假性缺氧，这是一个重要的肿瘤支持事件，是常氧下缺氧诱导因子(HIF)的激活。在SDH或FH缺乏的细胞中，HIF的激活是由于HIF1α分别被琥珀酸或富马酸稳定，当两者超过时，都会抑制HIFαPro羟基酶(PhD)。为了重新激活PHD，我们重点研究了它的底物--α-酮戊二酸。我们设计和合成了细胞渗透性的α-酮戊二酸衍生物，这种衍生物在TCA循环障碍的细胞中快速和优先地积聚。这项研究表明，琥珀酸或富马酸介导的对PHD的抑制是竞争性的，并被药理上升高细胞内α-酮戊二酸逆转。α-酮戊二酸衍生物的引入使SDH抑制的细胞恢复了正常的PHD活性和HIF1α水平，表明了与TCA循环功能障碍相关的癌症的新治疗可能性。
Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are components of the tricarboxylic acid (TCA) cycle and tumor suppressors. Loss of SDH or FH induces pseudohypoxia, a major tumor-supporting event, which is the activation of hypoxia-inducible factor (HIF) under normoxia. In SDH- or FH-deficient cells, HIF activation is due to HIF1 alpha stabilization by succinate or fumarate, respectively, either of which, when in excess, inhibits HIF alpha prolyl hydroxylase (PHD). To reactivate PHD, we focused on its substrate, alpha-ketoglutarate. We designed and synthesized cell-permeating alpha-ketoglutarate derivatives, which build up rapidly and preferentially in cells with a dysfunctional TCA cycle. This study shows that succinate- or fumarate-mediated inhibition of PHD is competitive and is reversed by pharmacologically elevating intracellular alpha-ketoglutarate. Introduction of alpha-ketoglutarate derivatives restores normal PHD activity and HIF1 alpha levels to SDH-suppressed cells, indicating new therapy possibilities for the cancers associated with TCA cycle dysfunction.