Functional characterization of the ectopically expressed olfactory receptor 2AT4 in human myelogenous leukemia.
Functional characterization of the ectopically expressed olfactory receptor 2AT4 in human myelogenous leukemia.
复制标题
人髓质白血病中异位表达的嗅觉受体2AT4的功能表征。
DOI：
10.1038/cddiscovery.2015.70
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发表时间：
2016
影响因子：
7
通讯作者：
Hatt H
中科院分区：
文献类型：
--
作者：
Manteniotis S;Wojcik S;Brauhoff P;Möllmann M;Petersen L;Göthert JR;Schmiegel W;Dührsen U;Gisselmann G;Hatt H
嗅觉受体（OR）家族主要表达于鼻上皮。在过去的二十年中，OR家族的成员被检测到在人体的不同部位如肝癌、前列腺癌或肠癌细胞中功能性表达。本研究采用RT-PCR和新一代测序技术检测了几种OR基因在人慢性粒细胞白血病（CML）细胞系K562和临床诊断的急性髓细胞白血病（AML）患者的白色血细胞中的表达。通过钙成像，我们更详细地描述了一个OR（OR2AT 4）在白血病中的细胞生物学作用。在这两种细胞系统中，OR2AT4激动剂Sandalore通过腺苷酸环化酶-cAMP-介导的途径引起强烈的Ca2+内流。OR2AT4拮抗剂Phenirat阻止了Sandalore诱导的细胞内Ca2+升高。Western blot和流式细胞术实验表明，OR2AT4的刺激通过降低p38-MAPK的磷酸化而抑制细胞增殖，并通过p44/42-MAPK的磷酸化而诱导细胞凋亡。此外，Sandalore增加了培养物中含血红蛋白细胞的数量。我们首次在CML和AML中描述了OR介导的通路，其可以在激活后调节增殖、凋亡和分化。这种机制为AML的治疗提供了新的治疗选择。
The olfactory receptor (OR) family was found to be expressed mainly in the nasal epithelium. In the last two decades members of the OR family were detected to be functional expressed in different parts of the human body such as in liver, prostate or intestine cancer cells. Here, we detected the expression of several ORs in the human chronic myelogenous leukemia (CML) cell line K562 and in white blood cells of clinically diagnosed acute myeloid leukemia (AML) patients by RT-PCR and next-generation sequencing. With calcium-imaging, we characterized in greater detail the cell biological role of one OR (OR2AT4) in leukemia. In both cell systems, the OR2AT4 agonist Sandalore-evoked strong Ca2+ influx via the adenylate cyclase-cAMP-mediated pathway. The OR2AT4 antagonist Phenirat prevented the Sandalore-induced intracellular Ca2+ increase. Western blot and flow cytometric experiments revealed that stimulation of OR2AT4 reduced the proliferation by decreasing p38-MAPK phosphorylation and induced apoptosis via phosphorylation of p44/42-MAPK. Furthermore, Sandalore increased the number of hemoglobin-containing cells in culture. We described for the first time an OR-mediated pathway in CML and AML that can regulate proliferation, apoptosis and differentiation after activation. This mechanism offers novel therapeutic options for the treatment of AML.