5-hydroxytryptamine drives apoptosis in biopsylike Burkitt lymphoma cells: reversal by selective serotonin reuptake inhibitors
5-hydroxytryptamine drives apoptosis in biopsylike Burkitt lymphoma cells: reversal by selective serotonin reuptake inhibitors
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DOI：
10.1182/blood.v99.7.2545
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发表时间：
2002-04-01
期刊：
影响因子：
20.3
通讯作者：
Gordon, J
中科院分区：
文献类型：
--
作者：
Serafeim, A;Grafton, G;Gordon, J
5-羟色胺（5-HT）是一种众所周知的中枢神经系统神经递质，参与免疫调节的各个方面。在这里，我们表明，5-HT可以有效地驱动程序性细胞死亡建立伯基特淋巴瘤（BL）线，保持忠实于原始活检表型（组1）。在5-HT存在下培养的第1组BL细胞表现出DNA合成的显著抑制，伴随着广泛的凋亡-5-羟色胺驱动的凋亡在24小时内完成，在此之前是早期半胱天冬酶激活，并且伴随着线粒体膜电位的下降，已经漂移到成淋巴细胞的第3组BL细胞表型对5-羟色胺的这些作用相对耐受，而bc 1 -2或bcl-X-L的异位表达对5-HT诱导的细胞凋亡具有明显的保护作用。5-HT受体拮抗剂（SDZ 205 -557、格拉司琼、麦西麦角）不能抑制阿托宁诱导的细胞凋亡，而选择性5-羟色胺再摄取抑制剂（SSRI）-氟西汀（百忧解）、帕罗西汀（Paxil）和西酞普兰（Celexa）-基本上阻断单胺作用。Western blot分析显示，BL细胞表达的蛋白质为！5-HT转运蛋白和转运试验证实了细胞对5-羟色胺的主动摄取。与神经元细胞不同的是，没有证据表明细胞内的氧化代谢产物是5-HT诱导的BL细胞程序性死亡的原因。这些数据表明，5-羟色胺通过主动转运机制进入后，可驱动活检样BL细胞凋亡，这为伯基特淋巴瘤提供了一种新的治疗方式。（血。2002;99：2545-2553）（C）2002由美国血液学学会。
Serotonin (5-HT), a well-known neurotransmitter of the central nervous system, has been implicated in diverse aspects of immune regulation. Here we show that 5-HT can efficiently drive programmed cell death in established Burkitt lymphoma (BL) lines that remain faithful to the original biopsy phenotype (group 1). Group 1 BL cells cultured in the presence of 5-HT exhibited marked suppression of DNA synthesis that was accompanied by extensive apoptosis-serotonin-driven apoptosis was complete within 24 hours, was preceded by early caspase activation, and was accompanied by a decline in mitochondrial membrane potential BL cells that had drifted to a lymphoblastic group 3 phenotype were relatively resistant to these actions of serotonin, and the forced ectopic expression of either bc1-2 or bcl-X-L provided substantial protection from 5-HT-induced apoptosis. 5-HT receptor antagonists (SDZ205-557, granisetron, methysergide) failed to inhibit serotonin-induced apoptosis, whereas the selective serotonin reuptake inhibitors (SSRI)-fluoxetine (Prozac), paroxetine (Paxil), and citalopram (Celexa)-substantially blocked the monoamine actions. Western blot analysis showed that BL cells expressed protein for the! 5-HT transporter, and transport assays confirmed active uptake of serotonin by the cells. Unlike what was suggested for neuronal cells, there was no evidence that intracellular oxidative metabolites were responsible for the 5-HTinduced programmed death of BL cells. These data indicate that serotonin drives apoptosis in biopsylike BL cells after its entry through an active transport mechanism, and they suggest a novel therapeutic modality for Burkitt lymphoma. (Blood. 2002;99:2545-2553) (C) 2002 by The American Society of Hematology.