Depletion of serotonin and selective inhibition of 2B receptor suppressed tumor angiogenesis by inhibiting endothelial nitric oxide synthase and extracellular signal-regulated kinase 1/2 phosphorylation.

Abstract

The effects of serotonin (5-HT) on tumor growth are inconsistent. We investigated whether a decreased level of 5-HT affected tumor growth using 5-HT transporter knockout (5-HTT(-/-)) mice, which showed 5-HT depletion. When cancer cells were injected subcutaneously into both 5-HTT(-/-) and 5-HTT(+/+) mice, the tumor growth was markedly attenuated in 5-HTT(-/-) mice. Serotonin levels in the blood, forebrain, and tumors of 5-HTT(-/-) mice bearing tumors were significantly smaller than those of their 5-HTT(+/+) littermates. However, 5-HT did not increase cancer cells' proliferation in vitro. When we applied 5-HTT inhibitors to the wild mice bearing tumors, they did not inhibit tumor growth. The endothelial nitric oxide synthase (eNOS) expressions in tumors were reduced in 5-HTT(-/-) mice compared with 5-HTT(+/+) mice. Stimulations with 5-HT (1-50 microM) induced eNOS expressions in human umbilical vein endothelial cell (HUVEC) in a concentration-dependent manner. When we measured activations of multiple signaling pathways by using a high-throughput phosphospecific antibodies platform, 5-HT stimulated the extracellular signal-regulated kinase 1/2 (ERK1/2) in HUVEC. Moreover, we found that the physiological level of 5-HT induced phosphorylation of both ERK1/2 and eNOS in HUVEC. Human umbilical vein endothelial cell expressed both 5-HT(2B) and 5-HT(2C) receptors. SB204741, a specific 5-HT(2B) receptor inhibitor, blocked 5-HT-induced ERK1/2 and eNOS phosphorylations, whereas RS102221, a specific 5-HT(2C) receptor inhibitor, did not in HUVEC. SB204741 reduced microvessel density in tumors and inhibited the proliferation of HUVEC in vitro. These results suggest that regulation of 5-HT and 5-HT receptors, especially the 5-HT(2B) receptor, may serve as a therapeutic strategy in cancer therapy.

• Authors: Masanori Asada, Satoru Ebihara, Shinsuke Yamanda, Kaijun Niu, Tatsuma Okazaki, Ichiro Sora, Hiroyuki Arai
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 11 Issue 4 Pg. 408-17 (Apr 2009) ISSN: 1476-5586 [Electronic] United States
• PMID: 19308295 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptor, Serotonin, 5-HT2B
• Serotonin Plasma Membrane Transport Proteins
• Serotonin
• Nitric Oxide Synthase Type III
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Endothelial Cells (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Fluorescent Antibody Technique
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Knockout
• Mice, Mutant Strains
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Neovascularization, Pathologic (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Phosphorylation
• Receptor, Serotonin, 5-HT2B (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Serotonin (metabolism)
• Serotonin Plasma Membrane Transport Proteins (deficiency, genetics)
• Signal Transduction (physiology)
• Umbilical Veins