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.
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.
Asada
Masanori
M
Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo-machi 4-1, Aoba-ku, Sendai 980-8575, Japan.
Ebihara
Satoru
S
Yamanda
Shinsuke
S
Niu
Kaijun
K
Okazaki
Tatsuma
T
Sora
Ichiro
I
Arai
Hiroyuki
H
D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D014471:Umbilical Veins
D044403:Receptor, Serotonin, 5-HT2B; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D052250:Nitric Oxide Synthase Type III; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3