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2‐Deoxy Glucose Modulates Expression and Biological Activity of VEGF in a SIRT‐1 Dependent Mechanism
Author(s) -
Kunhiraman Haritha,
Edatt Lincy,
Thekkeveedu Sruthi,
Poyyakkara Aswini,
Raveendran Viji,
Kiran Manikantan Syamala,
Sudhakaran Perumana,
Kumar Sameer V.B.
Publication year - 2017
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25629
Subject(s) - angiogenesis , glycolysis , anaerobic glycolysis , reprogramming , nad+ kinase , chemistry , cell culture , metastasis , microbiology and biotechnology , cancer cell , gene expression , cancer research , cell , biology , biochemistry , metabolism , cancer , gene , enzyme , genetics
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.