LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer.
LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer.
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DOI：
10.1158/1535-7163.mct-08-1049
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发表时间：
2009-03
影响因子：
5.7
通讯作者：
Seth P
中科院分区：
文献类型：
--
作者：
Xie H;Valera VA;Merino MJ;Amato AM;Signoretti S;Linehan WM;Sukhatme VP;Seth P
遗传性平滑肌瘤病和肾细胞癌（HLRCC）综合征的遗传基础是Krebs/三羧酸（TCA）循环酶、富马酸水合酶（FH）基因的种系失活突变，富马酸水合酶将富马酸转化为苹果酸。这些人易患皮肤和子宫平滑肌瘤以及高度侵袭性肾癌。抑制FH会导致氧化磷酸化（OXPHOS）的显著降低，这就需要糖酵解，然后丙酮酸发酵成乳酸，以提供足够的ATP和再生NAD+。此外，已知FH缺乏通过增强HIF转录物的稳定性来上调缺氧诱导因子（HIF）1 α的表达。这导致多种HIF调控基因的激活，包括血管内皮生长因子（VEGF）、葡萄糖转运蛋白GLUT1，以及几种糖酵解酶的表达增加。由于乳酸脱氢酶a （LDH-A）也是HIF1 α的靶标，促进发酵糖酵解（丙酮酸转化为乳酸），这是再生NAD+的必要步骤，我们想知道FH缺陷细胞是否对LDH-A阻断非常敏感。在这里，我们报道了HLRCC肿瘤确实过表达LDH-A；LDH-A抑制导致FH缺乏的细胞凋亡增加，并且这种作用是活性氧（ROS）介导的；在FH敲低的背景下，ldl - a敲低导致异种移植小鼠模型中肿瘤生长显著减少。
The genetic basis for the Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) syndrome is germline inactivating mutation in the gene for the Krebs/tricarboxylic acid (TCA) cycle enzyme, fumarate hydratase (FH), the enzyme that converts fumarate to malate. These individuals are predisposed to development of leiomyomas of the skin and uterus as well as highly aggressive kidney cancers. Inhibition of FH should result in significant decrease in oxidative phosphorylation (OXPHOS) necessitating that glycolysis followed by fermentation of pyruvate to lactate will be required to provide adequate ATP as well as to regenerate NAD+. Moreover, FH deficiency is known to upregulate expression of hypoxia inducible factor (HIF)1 α by enhancing the stability of HIF transcript. This leads to activation of various HIF regulated genes including vascular endothelial growth factor (VEGF), glucose transporter GLUT1, and increased expression of several glycolytic enzymes. Since lactate dehydrogenase-A (LDH-A), also a HIF1 α target, promotes fermentative glycolysis (conversion of pyruvate to lactate), a step essential for regenerating NAD+, we asked whether FH deficient cells would be exquisitely sensitive to LDH-A blockade. Here we report that HLRCC tumors indeed overexpress LDH-A; that LDH-A inhibition results in increased apoptosis in a cell with FH deficiency and that this effect is reactive oxygen species (ROS) mediated; and that LDH-A knockdown in the background of FH knockdown results in significant reduction in tumor growth in a xenograft mouse model.