MacKenzie Elaine D, Selak Mary A, Tennant Daniel A, Payne Lloyd J, Crosby Stuart, Frederiksen Casper M, Watson David G, Gottlieb Eyal
Cancer Research UK, The Beatson Institute for Cancer Research, Glasgow, Scotland G61 1BD, UK.
Mol Cell Biol. 2007 May;27(9):3282-9. doi: 10.1128/MCB.01927-06. Epub 2007 Feb 26.
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 HIF1alpha stabilization by succinate or fumarate, respectively, either of which, when in excess, inhibits HIFalpha 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 HIF1alpha levels to SDH-suppressed cells, indicating new therapy possibilities for the cancers associated with TCA cycle dysfunction.
琥珀酸脱氢酶（SDH）和延胡索酸水合酶（FH）是三羧酸（TCA）循环的组成部分和肿瘤抑制因子。SDH或FH的缺失会诱导假性缺氧，这是一种主要的肿瘤支持事件，即在常氧条件下缺氧诱导因子（HIF）的激活。在SDH或FH缺陷的细胞中，HIF激活分别是由于琥珀酸或延胡索酸使HIF1α稳定，这两种物质中的任何一种过量时都会抑制HIFα脯氨酰羟化酶（PHD）。为了重新激活PHD，我们将重点放在其底物α-酮戊二酸上。我们设计并合成了可穿透细胞的α-酮戊二酸衍生物，它们在TCA循环功能失调的细胞中迅速且优先积累。这项研究表明，琥珀酸或延胡索酸介导的对PHD的抑制是竞争性的，并且通过药理学方法提高细胞内α-酮戊二酸可将其逆转。引入α-酮戊二酸衍生物可使SDH抑制的细胞恢复正常的PHD活性和HIF1α水平，这表明与TCA循环功能障碍相关的癌症具有新的治疗可能性。
