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Autoregulatory effects of serotonin on proliferation and signaling pathways in lung and small intestine neuroendocrine tumor cell lines.

Abstract：

BACKGROUND:: Survival rates for gastrointestinal (GI) and bronchopulmonary (BP) neuroendocrine tumors (NETs) have not altered significantly (5-year survival rate: GI NETs, 64.1%; BP NETs, 87%-89%) in 30 years (from 1973 to 2004). No effective or specific antineoplastic agents are available to date, although somatostatin analogs inhibit NET 5-hydroxytryptophan (5-HT) secretion. Given the expression of 5-HT receptors on NETs, the authors hypothesized that 5-HT autoregulated NET proliferation. METHODS:: Proliferation was evaluated in 3 NET cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide uptake; in addition, real-time polymerase chain reaction analyses and enzyme-linked immunosorbent assay studies were performed to delineate 5-HT-mediated signaling pathways. To determine the receptor and role of endogenous 5-HT production, the effects of ketanserin (5-HT receptor subtypes 2A and 2C [5-HT(2A/2C)]); ondansetron (5-HT(3)); and the suicide inhibitor of the rate-limiting enzyme for 5-HT synthesis, tryptophan hydroxylase (7-HTP) were investigated. RESULTS:: Exogenously added 5-HT stimulated proliferation in atypical BP NET NCI-H720 cells (+50%; half-maximal stimulatory concentration [EC(50)] = 10 nM), in typical BP NET NCI-H727 cells (+40%; EC(50) = 0.01 nM), and in GI NET KRJ-I cells (+60%; EC(50) = 25 nM). In NCI-H720 cells, proliferation was inhibited by ketanserin (half-maximal inhibitory concentration [IC(50)] = 0.06 nM) and ondansetron (IC(50) = 0.4 nM) and also was inhibited by 7-HTP (IC(50) = 0.3 nM). In NCI-H727 cells, ketanserin and 7-HTP inhibited proliferation (IC(50) = 0.3 nM and IC(50) = 2.3 nM, respectively), whereas ondansetron had no effect. In KRJ-I cells, ketanserin (IC(50) = 0.1 nM) and 7-HTP (IC(50) = 0.6 nM), but not ondansetron, inhibited proliferation. In all cell lines, 5-HT activated proliferation through extracellular signal-regulated kinase 1 (ERK1) and ERK2 phosphorylation and c-Jun N-terminal kinase (JNK)-mediated pathways (c-JUN and Ki-67 transcription). An autoregulatory effect was indicated by the 7-HTP-mediated inhibition of extracellular 5-HT and downstream effects on NET proliferation. CONCLUSIONS:: Lung and GI NET proliferation was autoregulated by 5-HT through alterations in ERK and JNK signaling. Targeting NET cells with 5-HT(2) receptor antagonists and 7-HTP reversed proliferation. The current results indicated that 5-HT(2) receptor subtype-specific antagonists may represent a viable antiproliferative therapeutic strategy. Cancer 2009. (c) 2009 American Cancer Society.

journal_name

Cancer

journal_title

Cancer

authors

Drozdov I,Kidd M,Gustafsson BI,Svejda B,Joseph R,Pfragner R,Modlin IM

doi

10.1002/cncr.24533

subject

Has Abstract

pub_date

2009-11-01 00:00:00

pages

4934-45

issue

eissn

0008-543X

issn

1097-0142

journal_volume

115

pub_type

杂志文章

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Autoregulatory effects of serotonin on proliferation and signaling pathways in lung and small intestine neuroendocrine tumor cell lines.