Autoregulatory effects of serotonin on proliferation and signaling pathways in lung and small intestine neuroendocrine tumor cell lines.
Autoregulatory effects of serotonin on proliferation and signaling pathways in lung and small intestine neuroendocrine tumor cell lines.
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DOI：
10.1002/cncr.24533
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发表时间：
2009-11-01
期刊：
影响因子：
6.2
通讯作者：
Modlin, Irvin M.
中科院分区：
文献类型：
--
作者：
Drozdov, Ignat;Kidd, Mark;Gustafsson, Bjorn I.;Svejda, Bernhard;Joseph, Richard;Pfragner, Roswitha;Modlin, Irvin M.
关键词：
30年来（1973-2004），胃肠道（GI）和支气管肺（BP）神经内分泌肿瘤（NETs）的生存率没有显著变化（5年生存率分别为64.1%和87-89%）。虽然生长抑素类似物能抑制净血清素（5-HT）的分泌，但目前尚无有效或特异性的抗肿瘤药物。考虑到NET上5-HT受体的表达，我们假设5-HT自动调节NET的增殖。使用MTT摄取法评估三种NET细胞系的增殖情况，同时进行实时PCR和ELISA研究以描述5- ht介导的信号通路。为了确定内源性5-羟色胺产生的受体及其作用，研究了酮色胺（5-HT2A/C受体拮抗剂）、昂丹西酮（5-HT3拮抗剂）和自杀抑制剂7-羟色氨酸（7-HTP）的作用。外源性添加5-HT刺激了非典型BP-NET、NCI-H720 （+50%, EC50=10nM）、典型BP-NET、NCI-H727 （+40%, EC50=0.01nM）和GI-NET、KRJ-I （+60%, EC50=25nM）的增殖。ketanserin （IC50=0.06nM）、ondansetron （IC50=0.4nM）和7-HTP （IC50=0.3nM）均能抑制NCI-H720细胞的增殖。在NCI-H727中，酮色林和7-HTP抑制细胞增殖（IC50分别为0.3nM和2.3nM），而昂丹司琼无抑制作用。在krj - 1中，酮色林（IC50=0.1nM）和7-羟色胺（IC50=0.6nM）抑制增殖，而昂丹司琼没有抑制增殖。在所有细胞系中，5-HT通过ERK1/2磷酸化和jnk介导的途径（c-JUN和Ki67转录）激活增殖。7-羟色胺介导的细胞外5-羟色胺抑制和对NET增殖的下游影响表明了一种自调节作用。5-HT通过改变ERK和JNK信号自动调节肺和GI-NET的增殖。用5-HT2受体拮抗剂和7-HTP靶向NET细胞逆转增殖。5-HT2受体亚型特异性拮抗剂可能是一种可行的抗增殖治疗策略。
Survival rates for gastrointestinal (GI) and bronchopulmonary (BP) neuroendocrine tumors (NETs) have not significantly altered (5yr survival: 64.1% and 87–89%) in thirty years (1973–2004). No effective or specific anti-neoplastic agent(s) is available although somatostatin analogs inhibit NET serotonin (5-HT) secretion. Given the expression of 5-HT receptors on NETs, we hypothesized that 5-HT autoregulated NET proliferation. Proliferation was evaluated in three NET cell lines using MTT uptake while real-time PCR and ELISA 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-HT2A/C receptor antagonist), ondansetron (5-HT3 antagonist) and the suicide inhibitor 7-Hydroxytryptophan (7-HTP) were investigated. Exogenously added 5-HT stimulated proliferation in the atypical BP-NET, NCI-H720 (+50%, EC50=10nM), the typical BP-NET, NCI-H727 (+40%, EC50=0.01nM), and the GI-NET, KRJ-I (+60%, EC50=25nM). In NCI-H720, proliferation was inhibited by ketanserin (IC50=0.06nM) and ondansetron (IC50=0.4nM) as well as 7-HTP (IC50=0.3nM). In NCI-H727, ketanserin and 7-HTP inhibited proliferation (IC50=0.3nM and 2.3nM respectively) while ondansetron had no effect. In KRJ-I, ketanserin (IC50=0.1nM) and 7-HTP (IC50=0.6nM) but not ondansetron inhibited proliferation. In all cell lines, 5-HT activated proliferation through ERK1/2 phosphorylation and JNK-mediated pathways (c-JUN and Ki67 transcription). An auto-regulatory effect was indicated by 7-HTP-mediated inhibition of extracellular 5-HT and downstream effects on NET proliferation. Lung and GI-NET proliferation is autoregulated by 5-HT through alterations in ERK and JNK signaling. Targeting NET cells with 5-HT2 receptor antagonists and 7-HTP reversed proliferation. 5-HT2 receptor subtype-specific antagonists may represent a viable antiproliferative therapeutic strategy.
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影响因子：
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