GR 63799X, an EP3 receptor agonist, induced S phase arrest and 3T6 fibroblast growth inhibition
GR 63799X, an EP3 receptor agonist, induced S phase arrest and 3T6 fibroblast growth inhibition
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DOI：
10.1016/j.ejphar.2005.10.040
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发表时间：
2006-01-04
影响因子：
5
通讯作者：
Moreno, JJ
中科院分区：
文献类型：
--
作者：
Sanchez, T;Moreno, JJ
花生四烯酸代谢产物，特别是环氧合酶途径的代谢产物在细胞生长调控中的重要性早已被认识。最近，我们观察到前列腺素E-2（PGE（2））与EP 1和EP 4受体的相互作用参与了血清诱导的3 T6成纤维细胞生长，这是由于它们在细胞周期机制的不同水平上起作用。本研究表明，前列腺素EP 3受体在3 T6成纤维细胞中表达。我们研究了EP 3受体激动剂GR 63799 X在血清诱导的3 T6细胞增殖中的作用。这是浓度依赖性抑制（IC 50类似于10 μ M），达到完全抑制，无任何细胞毒性或促凋亡作用。前列腺素类EP 3受体激动剂处理减少了G（0）/G（1）和G（2）/M群体，而细胞在S期积聚。S期阻滞与细胞周期蛋白B水平降低和p21表达增强有关。我们的数据表明，在我们的实验条件下，EP 3激动剂降低cAMP水平。有趣的是，前列腺素类EP 3受体激动剂引起的S期阻滞似乎是cAMP依赖性的，至少部分是因为毛喉素治疗允许S期阻滞的细胞通过细胞周期并因此生长。因此，我们的研究结果表明，PGE 2 EP 3受体的相互作用可能参与血清诱导的3 T6成纤维细胞的生长，由于其对cAMP水平和细胞周期机制的S期的影响。(c)2005 Elsevier B. V.保留所有权利。
The importance of arachidonic acid metabolites on the control of cell growth, particularly those derived from cyclooxygenase pathway has long been recognized. Recently, we observed that prostaglandin E-2 (PGE(2)) interaction with EP1 and EP4 receptors is involved in serum-induced 3T6 fibroblast growth due to their effect at various levels of the cell cycle machinery. This study shows that prostanoid EP3 receptor was expressed in 3T6 fibroblast. We studied the role of EP3 receptor agonist GR 63799X in serum-induced 3T6 cell proliferation. This was concentration-dependent inhibit (IC50 similar to 10 mu M) to a complete inhibition without any cytotoxic or proapoptotic effect. The prostanoid EP3 receptor agonist treatment decreased the G(0)/G(1) and G(2)/M populations whereas cells were accumulated in S phase. This arrest in S phase was associated with a decrease in cyclin B levels and the enhancement of p21 expression. Our data show that EP3 agonist decreases cAMP levels in our experimental conditions. Interestingly, the S arrest caused by prostanoid EP3 receptor agonist seems to be cAMP dependent, at least in part, because forskolin treatment allowed S-arrested cells to progress through cell cycle and consequently growth. Thus, our results suggest that PGE2 EP3 receptor interaction may be involved in serum-induced 3T6 fibroblast growth due to their effects on cAMP levels and on cell cycle machinery of the S phase. (c) 2005 Elsevier B.V. All rights reserved.