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首页> 外文期刊>Journal of cellular biochemistry. >Paracrine stimulation of P2X7 receptor by ATP activates a proliferative pathway in ovarian carcinoma cells
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Paracrine stimulation of P2X7 receptor by ATP activates a proliferative pathway in ovarian carcinoma cells

机译：ATP旁分泌刺激P2X7受体激活卵巢癌细胞的增殖途径

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摘要

P2X7 is a purinergic receptor-channel; its activation by ATP elicits a broad set of cellular actions, from apoptosis to signals for survival. Here, P2X7 expression and function was studied in human ovarian carcinoma (OCA) cells, and biopsies from non-cancerous and cancer patients were analyzed by immunohistochemistry. Ovarian surface epithelium in healthy tissue expressed P2X7 at a high level that was maintained throughout the cancer. The cell lines SKOV-3 and CAOV-3 were used to investigate P2X7 functions in OCA. In SKOV-3 cells, selective stimulation of P2X7 by 2′(3′)-O-(4-benzoylbenzoyl) adenosine-5′-triphosphate (BzATP) induced a dose-dependent increase of intracellular Ca2+ concentration ([Ca2+]i) but not cell death. Instead, BzATP increased the levels of phosphorylated ERK and AKT (pERK and pAKT), with an EC50 of 44±2 and 1.27±0.5 μM, respectively; 10 μM BzATP evoked a maximum effect within 15 min that lasted for 120 min. Interestingly, basal levels of pERK and pAKT were decreased in the presence of apyrase in the medium, strongly suggesting an endogenous, ATP-mediated phenomenon. Accordingly: (i) mechanically stimulated cells generated a [Ca2+]i increase that was abolished by apyrase; (ii) apyrase induced a decrease in culture viability, as measured by the MTS assay for mitochondrial activity; and (iii) incubation with 10 μM AZ10606120, a specific P2X7 antagonist and transfection with the dominant negative P2X7 mutant E496A, both reduced cell viability to 70.1±8.9% and to 76.5±5%, respectively, of control cultures. These observations suggested that P2X7 activity was auto-induced through ATP efflux; this increased pERK and pAKT levels that generated a positive feedback on cell viability.
机译：P2X7是嘌呤能受体通道;它被ATP激活会引发一系列细胞作用，从凋亡到生存信号。在这里，研究了P2X7在人卵巢癌（OCA）细胞中的表达和功能，并通过免疫组织化学分析了来自非癌和癌症患者的活组织检查。健康组织中的卵巢表面上皮以高水平表达P2X7，并在整个癌症中得以维持。细胞系SKOV-3和CAOV-3用于研究OCA中P2X7的功能。在SKOV-3细胞中，2'（3'）-O-（4-苯甲酰基苯甲酰基）腺苷-5'-三磷酸（BzATP）选择性刺激P2X7诱导了细胞内Ca2 +浓度（[Ca2 +] i）的剂量依赖性增加。但不是细胞死亡。相反，BzATP增加了磷酸化ERK和AKT（pERK和pAKT）的水平，EC50分别为44±2和1.27±0.5μM。 10μMBzATP在15分钟内引起最大作用，持续120分钟。有趣的是，在培养基中存在腺苷三磷酸双磷酸酶的情况下，pERK和pAKT的基础水平降低，强烈暗示了内源性ATP介导的现象。因此：（i）机械刺激的细胞产生的[Ca2 +] i增加被腺苷三磷酸双磷酸酶消除; （ii）腺苷三磷酸酶诱导培养物活力的降低，如通过MTS测定的线粒体活性所测定的; （iii）与10μM的AZ10606120（一种特异的P2X7拮抗剂）孵育并用显性阴性P2X7突变体E496A转染，将细胞活力分别降低至对照培养物的70.1±8.9％和76.5±5％。这些观察结果表明，P2X7活性是通过ATP外排自动诱导的。这增加了pERK和pAKT的水平，从而对细胞活力产生了积极的反馈。

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