Sphingolipid modulation of angiogenic factor expression in neuroblastoma.

Abstract

Metabolism of sphingolipids into downstream lipid mediators followed by signaling modulates tumor microenvironment and the cancer cells to influence tumor progression. As such, sphingolipid signaling represents a novel way to modulate tumor biology. Neuroblastoma (NB), the most common extracranial solid tumor of childhood, is highly angiogenic and often displays poor prognosis. However, the role of sphingolipid mediators is not known in NB. We found that NB expresses high levels of sphingosine kinase-2, which is essential for the formation of sphingosine-1-phosphate (S1P). S1P induced VEGF expression in SK-N-AS NB cells. The effect occurred at the transcriptional level. Hypoxia in combination with S1P had a synergistic effect on VEGF expression. Strong correlation was detected between S1P receptor-2 (S1P(2)) and VEGF mRNAs in 11 different cell lines and 17 NB tissues. Blockade of S1P(2) with the selective antagonist JTE-013 significantly inhibited S1P-induced VEGF expression. Overexpression and knockdown of S1P(2) in SK-N-AS cells increased or inhibited S1P-induced VEGF secretion, respectively. Interestingly, JTE-013 significantly inhibited tumor growth, VEGF mRNA expression, and induced apoptosis in the NB tumor xenografts. Taken together, our data suggest that enhanced formation of sphingolipid mediator S1P in NB profoundly influences tumor microenvironment by inducing VEGF expression via S1P(2). Modulation of sphingolipid signaling by inhibiting S1P(2) may constitute a novel strategy to control NB.

• Authors: Mei-Hong Li, Timothy Hla, Fernando Ferrer
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 4 Issue 8 Pg. 1325-32 (Aug 2011) ISSN: 1940-6215 [Electronic] United States
• PMID: 21576349 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inducing Agents
• Lysophospholipids
• Platelet Endothelial Cell Adhesion Molecule-1
• Sphingolipids
• Vascular Endothelial Growth Factor A
• sphingosine 1-phosphate
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Sphingosine

Topics

• Angiogenesis Inducing Agents (metabolism)
• Animals
• Brain Neoplasms (metabolism)
• Cell Line, Tumor
• Enzyme-Linked Immunosorbent Assay (methods)
• Gene Expression Regulation, Neoplastic
• Humans
• Hypoxia (metabolism)
• In Situ Nick-End Labeling
• Lysophospholipids (metabolism)
• Male
• Mice
• Mice, Nude
• Neuroblastoma (metabolism)
• Phosphotransferases (Alcohol Group Acceptor) (metabolism)
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• Sphingolipids (metabolism)
• Sphingosine (analogs & derivatives, metabolism)
• Vascular Endothelial Growth Factor A (metabolism)