TY - JOUR
T1 - 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
AU - Asada, Masanori
AU - Ebihara, Satoru
AU - Yamanda, Shinsuke
AU - Niu, Kaijun
AU - Okazaki, Tatsuma
AU - Sora, Ichiro
AU - Arai, Hiroyuki
N1 - Funding Information:
Abbreviations: 5-HT, serotonin; 5-HTT, serotonin transporter; eNOS, endothelial nitric oxide synthase; LLC, Lewis lung carcinoma Address all correspondence to: Satoru Ebihara, MD, PhD, Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan. E-mail: sebihara@idac.tohoku.ac.jp 1This study was supported by Grants-In-Aid for Scientific Research from the Ministry of Education, Science, and Culture of the Japanese government to M. A. (no. 19790553) and to S. E. (nos. 18014004 and 19590688). 2This article refers to supplementary materials, which are designated by Figures W1 and W2 and are available online at www.neoplasia.com. Received 18 December 2008; Revised 21 January 2009; Accepted 21 January 2009 Copyright © 2009 Neoplasia Press, Inc. All rights reserved 1522-8002/09/$25.00 DOI 10.1593/neo.81630
PY - 2009/4
Y1 - 2009/4
N2 - 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.
AB - 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.
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U2 - 10.1593/neo.81.630
DO - 10.1593/neo.81.630
M3 - Article
C2 - 19308295
AN - SCOPUS:65549134709
VL - 11
SP - 408
EP - 417
JO - Neoplasia
JF - Neoplasia
SN - 1522-8002
IS - 4
ER -