EP4 mediates PGE2 dependent cell survival through the PI3 kinase/AKT pathway
EP4 mediates PGE2 dependent cell survival through the PI3 kinase/AKT pathway
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DOI：
10.1016/j.prostaglandins.2006.10.005
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发表时间：
2007-02-01
影响因子：
2.9
通讯作者：
Houchen, Courtney W.
中科院分区：
文献类型：
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作者：
George, Robert J.;Sturmoski, Mark A.;Houchen, Courtney W.
在用人T细胞白血病Jurkat细胞进行的实验中，在使用癌症化疗药物喜树碱处理之前，先用前列腺素E₂（5 nM）进行孵育，以此来检测前列腺素E₂的抗凋亡作用。通过检测细胞提取物中半胱天冬酶 - 3的活性以及碘化丙啶标记细胞的流式细胞术来评估细胞凋亡情况。用前列腺素E₂预孵育分别使喜树碱诱导的半胱天冬酶活性降低30%，使细胞凋亡减少35%。药理学数据表明，EP4受体负责介导对喜树碱诱导的细胞凋亡的保护作用。在使用前列腺素E₂和喜树碱之前，先用EP4拮抗剂（EP4A）对细胞进行预处理，可消除前列腺素E₂提高细胞存活率的作用。特异性抑制磷脂酰肌醇 - 3激酶或蛋白激酶B（AKT）/蛋白激酶的下游通路，但不抑制蛋白激酶A，可阻止前列腺素E₂引起的细胞存活率提高现象。这些发现对于前列腺素E₂受体特异性抑制在癌症治疗中的机制及潜在应用具有关键意义。（c）2006爱思唯尔公司。保留所有权利。
The anti-apoptotic effect of PGE(2) was examined in Jurkat cells (human T-cell leukemia) by incubation with PGE(2) (5 nM) prior to treatment with the cancer chemotherapeutic agent camptothecin. Apoptosis was evaluated by caspase-3 activity in cell extracts and flow cytometry of propidium iodide-labeled cells. Pre-incubation with PGE(2) reduced camptothecin-induced caspase activity by 30% and apoptosis by 35%, respectively. Pharmacological data demonstrate that the EP4 receptor is responsible for mediating the protection from camptothecin-induced apoptosis. Pre-treatment of the cells with the EP4 antagonist (EP4A) prior to PGE2 and camptothecin abolished the increased survival effect of PGE(2). Specific inhibition of the downstream of PI3 kinase or AKT/protein kinase but not protein kinase A prevents the observed increase in cell survival elicited by PGE(2). These findings have critical implications regarding the mechanism and potential application of PGE(2) receptor specific inhibition in cancer therapy. (c) 2006 Elsevier Inc. All rights reserved.