Nodal regulates energy metabolism in glioma cells by inducing expression of hypoxia-inducible factor 1α
Nodal regulates energy metabolism in glioma cells by inducing expression of hypoxia-inducible factor 1α
复制标题
DOI：
10.1093/neuonc/not086
复制
发表时间：
2013-10-01
期刊：
影响因子：
15.9
通讯作者：
Ma, Hsin-I
中科院分区：
文献类型：
--
作者：
Lai, Jing-Huei;Jan, Hsun-Jin;Ma, Hsin-I
背景葡萄糖代谢从氧化磷酸化转变为无氧糖酵解是恶性肿瘤细胞的生化标志。在本研究中，我们证明了Nodal刺激了人类胶质瘤癌细胞中糖酵解酶的表达，并降低了对线粒体氧化磷酸化的依赖。糖代谢的改变是由缺氧诱导因子（HIF）介导的。结蛋白表达与葡萄糖转运蛋白（Glut）-1、己糖激酶（HK）-II、丙酮酸脱氢酶激酶（PDK）-1的表达水平、丙酮酸脱氢酶（PDH）的磷酸化水平、葡萄糖摄取和乳酸积累相关。这些作用与线粒体耗氧量和ATP产生呈负相关。用特异性小发夹RNA敲低Nodal表达减少Glut-1、HK-II和PDK-1表达和PDH磷酸化。节点敲低还减少葡萄糖摄取和乳酸产生，这反过来又增加线粒体膜电位（Psi），O-2利用和ATP合成。Nodal在低表达Nodal胶质瘤细胞中的异位表达与Nodal敲低胶质瘤细胞的异位表达结果相反。用重组Nodal处理细胞增加HIF-1表达，并且这种作用在转录水平上受到调节。通过药理学抑制剂阻断Nodal受体或在U87 MG细胞中敲低Nodal可降低HIF-1 α表达。U87 MG细胞中HIF-1 α基因敲减可降低Glut-1、HK-II和PDK-1的表达及PDH磷酸化水平，这与Nodal基因敲减细胞中的结果相似。总之，这些结果表明Nodal通过HIF-1 alpha影响能量代谢。
Background. A shift in glucose metabolism from oxidative phosphorylation to anaerobic glycolysis is the biochemical hallmark of malignant cancer cells.Methods. In the present study, we demonstrated that Nodal stimulated the expression of glycolytic enzymes and decreased reliance on mitochondrial oxidative phosphorylation in human glioma cancer cells. The shift in glucose metabolism was mediated by induction of the hypoxia-inducible factor (HIF).Results. Nodal protein expression was shown to be correlated with expression levels of glucose transporter (Glut)-1, hexokinase (HK)-II, pyruvate dehydrogenase kinase (PDK)-1, the phosphorylation level of pyruvate dehydrogenase (PDH), glucose uptake, and lactate accumulation in human glioma cells. These effects were inversely correlated with mitochondrial oxygen consumption and ATP production. Knockdown of Nodal expression with specific small hairpin RNA reduced Glut-1, HK-II, and PDK-1 expressions and PDH phosphorylation. Nodal knockdown also reduced glucose uptake and lactate generation, which in turn increased mitochondrial membrane potential (Psi), O-2 utilization, and ATP synthesis. The ectopic expression of Nodal in low-expressing Nodal glioma cells resulted in the opposite results compared with those of Nodal knockdown glioma cells. Treatment of cells with recombinant Nodal increased HIF-1 expression, and this effect was regulated at the transcriptional level. Blockage of the Nodal receptor by a pharmacological inhibitor or Nodal knockdown inU87MGcells decreased HIF-1 alpha expression. Furthermore, HIF-1 alpha knockdown in U87MG cells decreased Glut-1, HK-II, and PDK-1 expressions and PDH phosphorylation, which were similar to results in Nodal knockdown cells.Conclusion. Taken together, these results suggest that Nodal affects energy metabolism through HIF-1 alpha.