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 phosphorylation1

Masanori Asada, Satoru Ebihara, Shinsuke Yamanda, Kaijun Niu, Tatsuma Okazaki, Ichiro Sora, Hiroyuki Arai

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

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-HTT1' mice bearing tumors were significantly smaller than those of their 5-HTT+ littermates. However, 5-HT did not increase cancer cells' pro- liferation 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 com- pared with 5-HTT+/+ mice. Stimulations with 5-HT (1-50 LiM) 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 phosphory- lation 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 phosphoryla- tions, 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.

Original languageEnglish
Pages (from-to)408-417
Number of pages10
JournalNeoplasia
Volume11
Issue number4
DOIs
Publication statusPublished - 2009 Apr

ASJC Scopus subject areas

  • Cancer Research

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