Corresponding Authors: Horng-Mo Lee, PhD, Department of Medical Laboratory Sciences and Biotechnology, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan.
Neuro Oncol. 2013 Oct;15(10):1330-41. doi: 10.1093/neuonc/not086. Epub 2013 Aug 1.
A shift in glucose metabolism from oxidative phosphorylation to anaerobic glycolysis is the biochemical hallmark of malignant cancer cells.
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).
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 (Ψ), O2 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 in U87MG cells decreased HIF-1α expression. Furthermore, HIF-1α 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.
Taken together, these results suggest that Nodal affects energy metabolism through HIF-1α.
从氧化磷酸化到无氧糖酵解的葡萄糖代谢转变是恶性癌细胞的生化标志。
在本研究中，我们证明了 Nodal 刺激人神经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。葡萄糖代谢的转变是由缺氧诱导因子（HIF）的诱导介导的。
Nodal 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、丙酮酸脱氢酶（PDH）的磷酸化水平、葡萄糖摄取和人神经胶质瘤细胞中的乳酸积累相关。这些效应与线粒体耗氧量和 ATP 生成呈负相关。用特异性短发夹 RNA 敲低 Nodal 表达可降低 Glut-1、HK-II 和 PDK-1 的表达和 PDH 的磷酸化。Nodal 敲低还降低了葡萄糖摄取和乳酸生成，这反过来又增加了线粒体膜电位（Ψ）、O2 利用和 ATP 合成。在低表达 Nodal 的神经胶质瘤细胞中过表达 Nodal 导致与 Nodal 敲低神经胶质瘤细胞相反的结果。用重组 Nodal 处理细胞会增加 HIF-1 的表达，这种作用在转录水平上受到调节。用药理学抑制剂阻断 Nodal 受体或在 U87MG 细胞中敲低 Nodal 会降低 HIF-1α 的表达。此外，在 U87MG 细胞中敲低 HIF-1α 会降低 Glut-1、HK-II 和 PDK-1 的表达和 PDH 的磷酸化，这与 Nodal 敲低细胞的结果相似。
综上所述，这些结果表明 Nodal 通过 HIF-1α 影响能量代谢。
