2-Deoxy Glucose Modulates Expression and Biological Activity of VEGF in a SIRT-1 Dependent Mechanism.
Reprogramming of energy metabolism particularly switching over of cells to aerobic glycolysis leading to accumulation of lactate is a hallmark of cancer. Lactate can induce angiogenesis, an important process underlying tumor growth and metastasis. VEGF is one of the most important cytokines which regulate this process and the present study was designed to examine if blocking glycolytic pathway in tumor cells can affect its angiogenic potency with respect to VEGF. For this, the expression and biological activity of VEGF synthesized and secreted by tumor derived cell lines in the presence or absence of 2-deoxy glucose (2-DG), an inhibitor of glycolysis was determined. The results suggested that inhibition of glycolysis using sub-lethal doses of 2-DG down-regulated the expression of VEGF and also significantly reduced its biological activity. Further mechanistic studies revealed that the down regulation of VEGF gene expression by 2-DG was due to an increase in SIRT-1 activity and the reduced biological activity was found to be due to an increase in the PAR modification of VEGF. Activity of SIRT-1 and PAR modification of VEGF in turn, was found to be correlated to the cellular NAD+levels. The results presented here therefore suggest that treatment of cancer cells with 2-DG can significantly reduce its overall angiogenic potency through transcriptional and post-translational mechanisms. J. Cell. Biochem. 118: 252-262, 2017. © 2016 Wiley Periodicals, Inc.
Department of Biochemistry and Molecular Biology, Central University of Kerala, Kasargod, India.
Haritha
H
Kunhiraman
Department of Biochemistry and Molecular Biology, Central University of Kerala, Kasargod, India.
Lincy
L
Edatt
Department of Biochemistry and Molecular Biology, Central University of Kerala, Kasargod, India.
Sruthi
S
Thekkeveedu
Department of Biochemistry and Molecular Biology, Central University of Kerala, Kasargod, India.
Aswini
A
Poyyakkara
Department of Plant Science, Central University of Kerala, Kasargod, India.|IUCGGT, University of Kerala, Karyavattom, Trivandrum, India.
Viji
V
Raveendran
Central Leather Research Institute, Chennai, India.
Manikantan Syamala
MS
Kiran
IUCGGT, University of Kerala, Karyavattom, Trivandrum, India.|Department of Computational Biology and Bioinformatics, University of Kerala, Karyavattom, Trivandrum, India.
Perumana
P
Sudhakaran
Department of Biochemistry and Molecular Biology, Central University of Kerala, Kasargod, India.
Sameer V B
SV
Kumar
D000818:Animals; D002642:Chick Embryo; D003847:Deoxyglucose / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
D009363:Neoplasm Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D003847:Deoxyglucose; C447939:SIRT1 protein, human; D056564:Sirtuin 1
ANGIOGENESIS; GLYCOLYSIS; POLY ADP RIBOSYLATION; SIRT-1; VEGF