PMID- 23911596
OWN - NLM
STAT- MEDLINE
DCOM- 20140502
LR  - 20211021
IS  - 1523-5866 (Electronic)
IS  - 1522-8517 (Print)
IS  - 1522-8517 (Linking)
VI  - 15
IP  - 10
DP  - 2013 Oct
TI  - Nodal regulates energy metabolism in glioma cells by inducing expression of 
      hypoxia-inducible factor 1alpha.
PG  - 1330-41
LID - 10.1093/neuonc/not086 [doi]
AB  - 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), 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-1alpha 
      expression. Furthermore, HIF-1alpha 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-1alpha.
FAU - Lai, Jing-Huei
AU  - Lai JH
AD  - 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. leehorng@tmu.edu.tw Hsin-I Ma, Department of 
      Neurological Surgery, Tri-Service General Hospital, National Defense Medical 
      Center, No.325, Sec.2, Chenggong Rd., Neihu District, Taipei 114, Taiwan, ROC.
FAU - Jan, Hsun-Jin
AU  - Jan HJ
FAU - Liu, Li-Wen
AU  - Liu LW
FAU - Lee, Chin-Cheng
AU  - Lee CC
FAU - Wang, Shyang-Guang
AU  - Wang SG
FAU - Hueng, Dueng-Yuan
AU  - Hueng DY
FAU - Cheng, Yung-Yen
AU  - Cheng YY
FAU - Lee, Horng-Mo
AU  - Lee HM
FAU - Ma, Hsin-I
AU  - Ma HI
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130801
PL  - England
TA  - Neuro Oncol
JT  - Neuro-oncology
JID - 100887420
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (NODAL protein, human)
RN  - 0 (Nodal Protein)
RN  - 0 (RNA, Small Interfering)
RN  - 33X04XA5AT (Lactic Acid)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 1.13.12.- (Luciferases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Blotting, Western
MH  - Brain Neoplasms/metabolism/pathology
MH  - *Energy Metabolism
MH  - Glioma/*metabolism/*pathology
MH  - Glucose/metabolism
MH  - Glycolysis
MH  - Humans
MH  - Hypoxia/metabolism/pathology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Lactic Acid/metabolism
MH  - Luciferases/metabolism
MH  - Membrane Potential, Mitochondrial
MH  - Mitochondria/*metabolism
MH  - Nodal Protein/antagonists & inhibitors/genetics/*metabolism
MH  - Oxygen Consumption
MH  - RNA, Small Interfering/genetics
MH  - Tumor Cells, Cultured
PMC - PMC3779039
OTO - NOTNLM
OT  - Glut-1
OT  - HIF-1
OT  - Nodal
OT  - energy metabolism
OT  - gliomas
EDAT- 2013/08/06 06:00
MHDA- 2014/05/03 06:00
PMCR- 2014/10/01
CRDT- 2013/08/06 06:00
PHST- 2013/08/06 06:00 [entrez]
PHST- 2013/08/06 06:00 [pubmed]
PHST- 2014/05/03 06:00 [medline]
PHST- 2014/10/01 00:00 [pmc-release]
AID - not086 [pii]
AID - 10.1093/neuonc/not086 [doi]
PST - ppublish
SO  - Neuro Oncol. 2013 Oct;15(10):1330-41. doi: 10.1093/neuonc/not086. Epub 2013 Aug 
      1.