VEGF Promotes Glycolysis in Pancreatic Cancer via HIF1α Up-Regulation

Background: Vascular endothelial growth factor (VEGF) is highly expressed in many types of tumors, including pancreatic cancer. Tumor cell-derived VEGF promotes angiogenesis and tumor progression. However, the role of VEGF in glucose metabolism remains unclear. Objective: We investigated the role and the underlying mechanism of VEGF in the glucose metabolism of pancreatic cancer cells. Method: Pancreatic cancer cells were stimulated with VEGF(165) for 1 or 2 h. The oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) were measured using the Seahorse XF96 Extracellular Flux Analyzer. Glycolytic enzymes were detected by quantitative real-time PCR. Neuropilin 1 (NRP1) was silenced by shRNA in order to investigate its role in VEGF-induced glycolysis. Immunohistochemistry (IHC) was performed to identify the correlation among VEGF, NRP1 and hypoxia inducible factor 1 alpha (HIF1 alpha) in pancreatic cancer tissues. Results: VEGF stimulation led to a metabolic transition from mitochondrial oxidative phosphorylation to glycolysis in pancreatic cancer. HIF1 alpha and NRP1 protein levels were both increased after VEGF stimulation. The down-regulation of NRP1 reduced glycolysis in pancreatic cancer cells. NRP1 and VEGF levels both correlated with HIF1 alpha expression in pancreatic tumor tissues. Conclusion: VEGF enhances glycolysis in pancreatic cancer via HIF1 alpha up-regulation. NRP1 plays a key role in VEGF-induced glycolysis.