Journal
PEDIATRIC BLOOD & CANCER
Volume 62, Issue 4, Pages 581-586Publisher
WILEY
DOI: 10.1002/pbc.25348
Keywords
glycolysis; GRP-R; HIF-1; neuroblastoma; PDK4; VEGF
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Funding
- National Institutes of Health [R01 DK61470]
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BackgroundUnder normoxic conditions, cancer cells use aerobic glycolysis as opposed to glucose oxidation for energy production; this altered metabolism correlates with poor outcomes in neuroblastoma. Hypoxia-inducible factor-1 alpha (HIF-1) and pyruvate dehydrogenase kinase 4 (PDK4) regulate aerobic glycolysis, while pyruvate dehydrogenase phosphatase 2 (PDP2) promotes glucose oxidation. Here, we sought to determine whether gastrin-releasing peptide receptor (GRP-R) signaling regulates glucose metabolism. ProcedureNeuroblastoma cell lines, BE(2)-C and SK-N-AS, were used. PCR microararay for glucose metabolism was performed on GRP-R silenced cells. Target protein expression was validated using Western blotting and VEGF ELISA. Cobalt chloride (CoCl2) was used to induce chemical hypoxia. Efficacy of targeting PDK regulation in neuroblastoma was assessed using dichloroacetate (DCA) by conducting cell viability assays and Western blotting for apoptotic markers. ResultsSilencing GRP-R decreased HIF-1 expression and blocked VEGF expression and secretion in both normoxic and CoCl2 induced hypoxia. PCR array analysis identified that GRP-R silencing reduced PDK4 and increased PDP2 mRNA expression. These findings were validated by Western blotting. CoCl2 induced hypoxia increased VEGF secretion, HIF-1, and PDK4 expression. PDK4 silencing decreased HIF-1 expression and VEGF expression and secretion. DCA treatment decreased BE(2)-C and SK-N-AS proliferation while promoting cell death. GRP-R silencing and DCA treatment synergistically halted BE(2)-C proliferation. ConclusionsWe report that GRP-R regulates glucose metabolism in neuroblastoma by modulating HIF-1, PDK4 and PDP2. PDK4 regulates glucose metabolism, in part, via regulation of HIF-1. Synergistic consequences of GRP-R inhibition and DCA treatment may suggest a novel therapeutic strategy for the treatment of aggressive neuroblastoma. Pediatr Blood Cancer 2015;62:581-586. (c) 2015 Wiley Periodicals, Inc.
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