Interplay between the prostaglandin transporter OATP2A1 and prostaglandin E2-mediated cellular effects
Interplay between the prostaglandin transporter OATP2A1 and prostaglandin E2-mediated cellular effects
复制标题
DOI：
10.1016/j.cellsig.2014.11.027
复制
发表时间：
2015-03-01
影响因子：
4.8
通讯作者：
Mandery, Kathrin
中科院分区：
文献类型：
--
作者：
Bujok, Krystyna;Glaeser, Hartmut;Mandery, Kathrin
前列腺素如前列腺素E-2（PGE（2））在胃粘膜的生理和病理生理通路中起着关键作用。关于胃粘膜和胃癌中前列腺素E（EP）受体与前列腺素转运蛋白OATP 2A 1的相互关系知之甚少。因此，我们首先研究了OATP 2A 1和EP 4在正常胃粘膜和胃癌中的表达。使用人胚肾细胞（HEK 293）和OATP 2A 1稳定转染的人胃癌细胞系AGS研究了不同的PGE（2）介导的细胞途径和机制。OATP 2A 1和EP 4在正常胃组织和胃癌组织中共定位和表达。在过表达EP 4和OATP 2A 1的HEK 293和AGS细胞中，OATP 2A 1可降低PGE（2）介导的cAMP生成。AGS细胞中OATP 2A 1的表达导致[H-3]-胸苷掺入减少，这与AGS-OATP 2A 1细胞在细胞周期S期的蓄积高于对照细胞一致。相反，与对照细胞相比，HEK 293细胞中OATP 2A 1的表达对S期的分布没有影响。OATP 2A 1还减少了AGS-OATP 2A 1细胞中PGE（2）介导的白细胞介素-8 mRNA（IL-8）和缺氧诱导因子1 α（HIF 1 α）蛋白的表达。OATP 2A 1的表达增加了AGS细胞对伊立替康的敏感性，导致细胞活力降低。综上所述，这些数据表明OATP 2A 1影响PGE（2）介导的细胞途径。因此，OATP 2A 1需要被认为是一个关键的决定因素，了解的生理和病理生理学的三尖杉酯碱在健康和肿瘤胃粘膜。(C)2014 Elsevier Inc. All rights reserved.
Prostaglandins such as prostaglandin E-2 (PGE(2)) play a pivotal role in physiological and pathophysiological pathways in gastric mucosa. Little is known about the interrelation of the prostaglandin E (EP) receptors with the prostaglandin transporter OATP2A1 in the gastric mucosa and gastric carcinoma. Therefore, we first investigated the expression of OATP2A1 and EP4 in normal and carcinoma gastric mucosa. Different PGE(2)-mediated cellular pathways and mechanisms were investigated using human embryonic kidney cells (HEK293) and the human gastric carcinoma cell line AGS stably transfected with OATP2A1. Colocalization and expression of OATP2A1 and EP4 were detected in mucosa of normal gastric tissue and of gastric carcinomas. OATP2A1 reduced the PGE(2)-mediated cAMP production in HEK293 and AGS cells overexpressing EP4 and OATP2A1. The expression of OATP2A1 in AGS cells resulted in a reduction of [H-3]-thymidine incorporation which was in line with a higher accumulation of AGS-OATP2A1 cells in S-phase of the cell cycle compared to control cells. In contrast, the expression of OATP2A1 in HEK293 cells had no influence on the distribution in the S-phase compared to control cells. OATP2A1 also diminished the PGE(2)-mediated expression of interleukin-8 mRNA (IL-8) and hypoxia-inducible-factor 1 alpha (HIF1 alpha) protein in AGS-OATP2A1 cells. The expression of OATP2A1 increased the sensitivity of AGS cells against irinotecan which led to reduced cell viability. Taken together, these data show that OATP2A1 influences PGE(2)-mediated cellular pathways. Therefore, OATP2A1 needs to be considered as a key determinant for the understanding of the physiology and pathophysiology of prostaglandins in healthy and tumorous gastric mucosa. (C) 2014 Elsevier Inc. All rights reserved.