Role of arachidonic acid metabolites on the control of non-differentiated intestinal epithelial cell growth
Role of arachidonic acid metabolites on the control of non-differentiated intestinal epithelial cell growth
复制标题
DOI：
10.1016/j.biocel.2013.05.009
复制
发表时间：
2013-08-01
影响因子：
4
通讯作者：
Moreno, Juan J.
中科院分区：
文献类型：
--
作者：
Cabral, Marisol;Martin-Venegas, Raquel;Moreno, Juan J.
越来越多的证据表明，花生四烯酸（AA）级联反应的酶、受体和代谢产物在肠上皮细胞增殖和结直肠肿瘤发生中起作用。然而，现有的资料并不能提供完整的情况，而且存在一些差异。因此，深入研究AA级联反应对肠上皮细胞生长的影响可能是适当的。我们的数据显示，用10%胎牛血清（FBS）培养的未分化Caco-2细胞合成可观量的前列腺素E-2（PGE（2））、白三烯B-4（LTB 4）和5-、12和15-羟基二十碳四烯酸（HETE），但不合成LTD 4、20-HETE和环氧二十碳三烯酸。我们还发现PGE（2）、LTB_4和5-、12-、15-HETE合成的抑制剂以及PGE（2）和LTB_4的受体拮抗剂可阻断10%FBS诱导的Caco-2细胞生长和DNA合成，而无细胞毒性或凋亡活性。有趣的是，在10%FBS Caco-2培养物中达到的浓度（1-10 nM）的PGE（2）、LTB 4和5-、12-和15-HETE能够诱导Caco-2细胞生长和DNA合成。这是由于PGE（2）与EP 1和EP 4受体以及LTB 4和HETE与BLT 1和BLT 2受体的相互作用。此外，我们提供的证据表明，PGE（2）刺激几种细胞信号通路，如ERK，P38 α，CREB和GSKP/β-连环蛋白参与Caco-2生长的调节。最后，我们提供的证据表明，LTB 4和HETE的促有丝分裂作用可以依赖于，至少部分依赖于PGE（2）的合成。(C)2013爱思唯尔有限公司保留所有权利。
Increasingly evidence indicates that enzymes, receptors and metabolites of the arachidonic acid (AA) cascade play a role in intestinal epithelial cell proliferation and colorectal tumorigenesis. However, the information available does not provide a complete picture and contains a number of discrepancies. For this reason it might be appropriate a thorough study into the impacts of the AA cascade on intestinal epithelial cell growth. Our data show that non-differentiated Caco-2 cells cultured with 10% fetal bovine serum (FBS) synthesize appreciable amounts of prostaglandin E-2 (PGE(2)), leukotriene B-4 (LTB4) and 5-, 12 and 15-hydroxyeicosatetraenoic acid (HETE) but not LTD4, 20-HETE and epoxyeicosatrienoic acids. We also found that inhibitors of PGE(2), LTB4 arid 5-, 12-, 15-HETE synthesis as well as receptor antagonists of PGE(2) and LTB4 blocked Caco-2 cell growth and DNA synthesis induced by 10% FBS without cytotoxic or apoptotic activity. Interestingly, PGE(2), LTB4 and 5-, 12- and 15-HETE at concentrations reached in 10% FBS Caco-2 cultures (1-10 nM) were able to induce Caco-2 cell growth and DNA synthesis. This was due to the interaction of PGE(2) with EP1 and EP4 receptors and LTB4 and HETEs with BLT1 and BLT2 receptors. Moreover, we provide evidence that PGE(2) stimulates several cell signaling pathways such as ERK, P38 alpha, CREB and GSKP/beta-catenin involved in the regulation of Caco-2 growth. Finally, we provide evidence that the mitogenic effects of LTB4 and HETEs can be dependent, at least in part, on PGE(2) synthesis. (C) 2013 Elsevier Ltd. All rights reserved.