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

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ID: 199759
2009
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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 µM) 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-HT2B and 5-HT2C receptors. SB204741, a specific 5-HT2B receptor inhibitor, blocked 5-HT-induced ERK1/2 and eNOS phosphorylations, whereas RS102221, a specific 5-HT2C 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-HT2B receptor, may serve as a therapeutic strategy in cancer therapy.
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asada2009neoplasia:depletion Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Masanori Asada;Satoru Ebihara;Shinsuke Yamanda;Kaijun Niu;Tatsuma Okazaki;Ichiro Sora;Hiroyuki Arai
Journal ACS chemical neuroscience
Year 2009
DOI
10.1593/neo.81630
URL
http://www.sciencedirect.com/science/article/pii/S1476558609800699
Keywords
neoplasms Oncology including cancer and carcinogens tumors

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