Nodal regulates energy metabolism in glioma cells by inducing expression of hypoxia-inducible factor 1

Jing Huei Lai, Hsun Jin Jan, Li Wen Liu, Chin Cheng Lee, Shyang Guang Wang, Dueng Yuan Hueng, Yung Yen Cheng, Horng Mo Lee, Hsin I. Ma

研究成果: 雜誌貢獻文章同行評審

18 引文 斯高帕斯(Scopus)

摘要

BackgroundA shift in glucose metabolism from oxidative phosphorylation to anaerobic glycolysis is the biochemical hallmark of malignant cancer cells.MethodsIn 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).ResultsNodal 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-1 expression. Furthermore, HIF-1 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.ConclusionTaken together, these results suggest that Nodal affects energy metabolism through HIF-1.
原文英語
頁(從 - 到)1330-1341
頁數12
期刊Neuro-Oncology
15
發行號10
DOIs
出版狀態已發佈 - 十月 2013

ASJC Scopus subject areas

  • 癌症研究
  • 腫瘤科
  • 神經病學(臨床)

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