Altered purinergic receptor-Ca2+ signaling associated with hypoxia-induced epithelial-mesenchymal transition in breast cancer cells
Altered purinergic receptor-Ca2+ signaling associated with hypoxia-induced epithelial-mesenchymal transition in breast cancer cells
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DOI：
10.1016/j.molonc.2015.09.006
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发表时间：
2016-01-01
影响因子：
6.6
通讯作者：
Monteith, Gregory R.
中科院分区：
文献类型：
--
作者：
Azimi, Iman;Beilby, Hannah;Monteith, Gregory R.
缺氧是许多癌症微环境的一个特征，并可触发上皮间充质转化（EMT），这一过程使细胞获得更具侵袭性的表型，从而提高存活率。在MDA-MB-468乳腺癌细胞中，腺苷5'-三磷酸（ATP）通过嘌呤能受体诱导的Ca2+信号的重塑与表皮生长因子（EGF）诱导的EMT有关。在这里，我们在MDA-MB-468细胞缺氧诱导的EMT模型中评估了ATP介导的Ca2+信号。与EGF一样，缺氧处理（1% O-2）也与MDA-MB-468细胞对ATP的敏感性显著降低相关（常氧细胞的EC50为0.5 μ M，而缺氧细胞的EC50为5.8 μ M）。缺氧后对P2X和P2Y嘌呤能受体mRNA水平的评估显示了一系列嘌呤能受体水平的变化。P2X4、P2X5、P2X7、P2Y1和P2Y11 mRNA随缺氧降低，而P2Y6 mRNA升高。P2Y6上调是生长因子和缺氧诱导的EMT模型的共同特征。与其他亚型相比，基底样乳腺肿瘤中P2Y6水平也显著升高，P2Y6水平较高的乳腺癌患者总体生存率降低。P2Y6 sirna介导的沉默和P2Y6药理学抑制剂MRS2578可降低MDA-MB468细胞中缺氧诱导的波形蛋白表达。P2Y6抑制也减少了间充质样MDA-MB-231乳腺癌细胞的迁移。P2Y6的上调似乎是乳腺癌细胞间充质表型的共同特征，抑制该受体可能是乳腺癌转移的新治疗靶点。(C) 2015年欧洲生化学会联合会。Elsevier B.V.版权所有。
Hypoxia is a feature of the microenvironment of many cancers and can trigger epithelialmesenchymal transition (EMT), a process by which cells acquire a more invasive phenotype with enriched survival. A remodeling of adenosine 5'-triphosphate (ATP)-induced Ca2+ signaling via purinergic receptors is associated with epidermal growth factor (EGF)induced EMT in MDA-MB-468 breast cancer cells. Here, we assessed ATP -mediated Ca2+ signaling in a model of hypoxia-induced EMT in MDA-MB-468 cells. Like EGF, hypoxia treatment (1% O-2) was also associated with a significant reduction in the sensitivity of MDA-MB-468 cells to ATP (EC50 of 0.5 mu M for normoxic cells versus EC50 of 5.8 mu M for hypoxic cells). Assessment of mRNA levels of a panel of P2X and P2Y purinergic receptors following hypoxia revealed a change in levels of a suite of purinergic receptors. P2X4, P2X5, P2X7, P2Y1 and P2Y11 mRNAs decreased with hypoxia, whereas P2Y6 mRNA increased. Up regulation of P2Y6 was a common feature of both growth factor- and hypoxia-induced models of EMT. P2Y6 levels were also significantly increased in basal-like breast tumors compared to other subtypes and breast cancer patients with higher P2Y6 levels showed reduced overall survival rates. P2Y6 siRNA-mediated silencing and the P2Y6 pharmacological inhibitor MRS2578 reduced hypoxia-induced vimentin protein expression in MDA-MB468 cells. P2Y6 inhibition also reduced the migration of mesenchymal-like MDA-MB-231 breast cancer cells. The up-regulation of P2Y6 appears to be a common feature of the mesenchymal phenotype of breast cancer cells and inhibition of this receptor may represent a novel therapeutic target in breast cancer metastasis. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.