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2008 Annual Meeting Abstracts

Sphingosine-1-phosphate upregulates vascular endothelial growth factor expression in human neuroblastoma cells via S1P2/ROCK/ERK pathway
Fernando Ferrer, MD1,2, Meihong Li, PhD2, Teresa Sanchez, PhD2, Tim Hla, PhD2.
1Connecticut Children's Medical Center, Hartford, CT, USA, 2University of Connecticut Health Center, Hartford, CT, USA.

Objective: Neuroblastoma, the most common extracranial solid tumor of childhood, presents with poor survival due to the occurrence of multidrug resistance and tumor metastasis. Bioactive lipid sphingosine-1-phosphate (S1P) and its five specific receptors (S1P1-5) have been implicated in many physiological and pathological processes including tumor growth and angiogenesis. However, little is known concerning the role of S1P in neuroblastoma.
Design: Neuroblastoma SK-N-AS cells were subjected to S1P and blockade of specific receptors using inhibitors JTE-013 (S1P2 inhibitor), VPC44116 (S1P1 inhibitor), Y27632 (ROCK inhibitor) and U0126 (ERK inhibitor). In addition, overexpression of S1P2 in SK-N-AS cells by adenoviral transduction was performed. In separate experiments, SK-N-AS cells were placed in hypoxia with S1P stimulation.
Main outcomes measures: VEGF mRNA expression and protein secretion was measured by quantitative RT PCR and VEGF ELISA analysis.
Results: In this study we found that S1P could induce vascular endothelial growth factor (VEGF) mRNA expression and protein secretion in SK-N-AS cells. Blockade of S1P2 with JTE-013 inhibited S1P-induced VEGF mRNA expression and protein secretion while S1P1 antagonist VPC44116 did not. In addition, overexpression of S1P2 in SK-N-AS cells further increased S1P-induced VEGF secretion compared to controls. To delineate the downstream signaling pathway, pharmacological inhibitors were used. We found that ROCK inhibitor Y27632 and ERK inhibitor U0126 completely blocked VEGF mRNA expression and potently inhibited S1P-induced VEGF secretion, suggesting that S1P-induced VEGF mRNA expression and protein secretion might be mediated by S1P2/ROCK/ERK pathway. Further, hypoxia together with S1P stimulation had an additive effect in increasing VEGF mRNA level and protein secretion.
Conclusions: Taken together, these data suggest that VEGF induced by S1P/S1P2 pathway might play a critical role in neuroblastoma growth and angiogenesis.


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