Manteniotis S, Wojcik S, Brauhoff P, Möllmann M, Petersen L, Göthert J R, Schmiegel W, Dührsen U, Gisselmann G, Hatt H
Department of Cell Physiology, Ruhr-University Bochum , Bochum, Germany.
Department of Hematology, University Hospital Essen , Essen, Germany.
Cell Death Discov. 2016 Jan 25;2:15070. doi: 10.1038/cddiscovery.2015.70. eCollection 2016.
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 Ca(2+) influx via the adenylate cyclase-cAMP-mediated pathway. The OR2AT4 antagonist Phenirat prevented the Sandalore-induced intracellular Ca(2+) 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.
嗅觉受体（OR）家族主要在鼻上皮中表达。在过去二十年中，人们发现OR家族成员在人体不同部位功能性表达，如在肝癌、前列腺癌或肠癌细胞中。在此，我们通过逆转录聚合酶链反应（RT-PCR）和下一代测序，检测了人类慢性髓性白血病（CML）细胞系K562以及临床诊断的急性髓性白血病（AML）患者白细胞中几种OR的表达。通过钙成像，我们更详细地研究了一种OR（OR2AT4）在白血病中的细胞生物学作用。在这两种细胞系统中，OR2AT4激动剂檀香醇通过腺苷酸环化酶 - cAMP介导的途径引起强烈的Ca(2+)内流。OR2AT4拮抗剂非尼拉阻止了檀香醇诱导的细胞内Ca(2+)增加。蛋白质印迹和流式细胞术实验表明，刺激OR2AT4可通过降低p38 - MAPK磷酸化来减少增殖，并通过p44/42 - MAPK磷酸化诱导细胞凋亡。此外，檀香醇增加了培养物中含血红蛋白细胞的数量。我们首次描述了CML和AML中一种由OR介导的途径，该途径在激活后可调节增殖、凋亡和分化。这一机制为AML的治疗提供了新的治疗选择。
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